Substituted benzimidazol-2-ones as vasopressin receptor antagonists and neuropeptide Y modulators

ABSTRACT

The invention is directed to substituted benzimidazol-2-ones of Formula I,                    
     wherein A, X, Y, m, n, R 1 , R 2 , R 3 , R 4 , and R 5  are as described in the specification, which are useful as vasopressin receptor antagonists or Neuropeptide Y Modulators for treating conditions such as aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, obesity, anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memory loss, sexual dysfunction, disorders of sleep and other circadian rhythms, and Cushing&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Ser. No. 60/243,817, filedOct. 27, 2000.

FIELD OF THE INVENTION

This invention relates to novel substituted benzimidazol-2-ones. Moreparticularly, the compounds of the present invention modulate thebinding of the peptide hormone vasopressin and neuropeptide Y to theirrespective receptors and are therefore useful for treating conditionsinvolving increased vascular resistance, cardiac insufficiency, anddisorders of energy metabolism.

BACKGROUND OF THE INVENTION

Vasopressin is a nonapeptide hormone that is secreted primarily from theposterior pituitary gland. The hormone effects its actions through thevascular V-1 and renal V-2 receptor subtypes. The functions ofvasopressin include contraction of uterine, bladder, and smooth muscle;stimulation of glycogen breakdown in the liver; induction of plateletaggregation; release of corticotropin from the anterior pituitary andstimulation of renal water reabsorption. As a neurotransmitter withinthe central nervous system (CNS), vasopressin can affect aggressivebehavior, sexual behavior, the stress response, social behavior andmemory. The V-1a receptor mediates central nervous system effects,contraction of smooth muscle and hepatic glycogenolytic effects ofvasopressin, while the V-1b receptor mediates anterior pituitary effectsof vasopressin. The V-2 receptor, presumably found only in the kidney,effects the antidiuretic actions of vasopressin via stimulation ofadenylate cyclase.

Elevated plasma vasopressin levels appear to play a role in thepathogenesis of congestive heart failure (P. A. Van Zwieten, Progr.Pharmacol. Clin. Pharmacol. 1990, 7, 49). As progress toward thetreatment of congestive heart failure, nonpeptide vasopressin V-2receptor antagonists have induced low osmolality aquaresis and decreasedperipheral resistance in conscious dogs with congestive heart failure(H. Ogawa, J. Med. Chem. 1996, 39, 3547). In certain pathologicalstates, plasma vasopressin levels may be inappropriately elevated for agiven osmolality, thereby resulting in renal water retention andhyponatremia. Hyponatremia, associated with edematous conditions(cirrhosis, congestive heart failure, renal failure), can be accompaniedby the syndrome of inappropriate secretion of antidiuretic hormone(SIADH). Treatment of SIADH-compromised rats with a vasopressin V-2antagonist has corrected their existing hyponatremia (G. Fujisawa,Kidney Int. 1993, 44(1), 19). Due in part to the contractile actions ofvasopressin at its V-1 receptor in the vasculature, vasopressin V-1antagonists have reduced blood pressure as a potential treatment forhypertension as well. Thus, vasopressin receptor antagonists are usefulas therapeutics in the conditions of hypertension, congestive heartfailure/cardiac insufficiency, coronary vasospasm, cardiac ischemia,liver cirrhosis, renal vasospasm, renal failure, cerebral edema andischemia, stroke, thrombosis, and water retention.

Several non-peptide arginine vasopressin (AVP) antagonists have beenreported. One of the V1a selective antagonists is known as OPC 21268(see J. Donald Albright and P. S. Chan, Current Pharm. Design, 1997, 3,615-632),

which is stated to be only active in rat with no activity when testedfor binding to human V1a receptor.

U.S. Pat. Nos. 5,849,780 and 5,585,394, both to Malta et. al., showcompounds of the following structures, respectively:

Sr-121463A is stated to be a potent selective orally active V2 receptorantagonist.

Neuropeptide Y (NPY) is a 36 residue, amidated polypeptide widelypresent in both the central and peripheral nervous systems. It is alsopresent in the cardiovascular system, platelets, endothelium, adrenalmedulla, pancreas, kidney and other organs. NPY binds to a number ofG-protein coupled receptors such as Y1, Y2, and Y3. The Y1 receptor isstimulated by NPY or PYY (Peptide YY) and believed to be the majorvascular receptor. The Y2 receptor is stimulated by C-terminal fragmentsof NPY or PYY and is abundantly expressed both centrally andperipherally. Present in adrenal medulla, heart, and brain stem, Y3 isexclusively responsive to NPY. Other subtypes of this receptor familyare also known to exist. NPY has a number of biological effects.Intranasal administration of NPY reduces nasal airway resistance andvascular permeability. NPY also plays an important role in modulatingthe cardiovascular system, behavior, anxiety and the secretion ofcertain hormones; it contributes to the central and peripheral controlof blood pressure, the regulation of feeding behavior, obesity, diabetesand psychiatric disorders.

It has been reported that Y1 agonists cause an increase in bloodpressure as well as feeding behavior. Y2 agonists/antagonists, on theother hand, can modulate neurotransmitter release.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by thefollowing Formula I:

wherein

A is aryl or heteroaryl having 0-4 heteroatoms selected from N, O, andS;

X is selected from S, O, NH, and NCN;

Y is S or O;

R₁ is 1-3 groups selected from hydrogen, alkyl, substituted alkyl,halogen, nitro, methylenedioxy, nitrile, —OR^(a), —NHR^(a),—NR^(a)R^(b), —S(O)_(p)R^(a), —N(R^(a))C(O)R^(b), —C(O)OR^(a),—C(O)NR^(a)R^(b), —SO₂NR^(a)R^(b), —N(R^(a))SO₂R^(b),N(R^(a))C(O)NR^(a), and NHCOOR^(a), wherein R^(a) and R^(b) areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl;

R₂ is selected from hydrogen, alkyl, and substituted alkyl;

R₃ is selected from hydrogen, alkyl, substituted alkyl, benzhydryl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, substituted heterocyclyl, —C(O)OR^(c), and—C(O)NR^(c)R^(d), wherein R^(c) and R^(d) are independently selectedfrom hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl, or NR^(c)R^(d) may be taken together to form a groupselected from heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl;

R₄ and R₅ are independently selected from hydrogen, alkyl, alkylsubstituted with aryl or heteroaryl, phenyl, substituted phenyl, or R₄and R₅ are non-existent when n is 0;

p is from 0 to 2;

n is 0 or 1; and

m is 0 or 1, with the proviso that when m is 0, X is O, and R₃ isselected from heteroaryl, substituted heteroaryl, —C(O)OR^(c), and—C(O)NR^(c)R^(d) wherein R^(c) and R^(d) are independently selected fromalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, orNR^(c)R^(d) may be taken together to form a group selected fromheteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl, then n is 0;

or an optical isomer, enantiomer, diastereomer, racemate thereof, or apharmaceutically acceptable salt thereof.

The compounds of the present invention are vasopressin receptorantagonists which are useful in disease states of inner ear disorders,aggression, obsessive-compulsive disorders, hypertension, hyperglycemia,dysmenorrhea, congestive heart failure/cardiac insufficiency, coronaryvasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renalfailure, cerebral edema and ischemia, stroke, thrombosis, waterretention, nephrotic syndrome, central nervous injuries, diabetes,anxiety, depression, stress, and/or Cushing's disease.

The compounds of the present invention are also Neuropeptide Ymodulators which are useful in disease states of hypertension,congestive heart failure/cardiac insufficiency, obesity, diabetes,anorexia, hyperglycemia, anxiety, depression, asthma, memory loss,sexual dysfunction, and disorders of sleep and other circadian rhythms.

An embodiment of the invention is a method of treating a conditionassociated with vasopressin receptor activity or Neuropeptide Y receptoractivity in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of any of the compounds orpharmaceutical compositions thereof.

An embodiment of the invention is a method of treating a conditionassociated with Neuropeptide Y receptor activity in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsthereof.

Another embodiment of the invention is a method of inhibiting the onsetof a condition associated with vasopressin receptor activity orNeuropeptide Y receptor activity in the subject, which comprisesadministering to the subject a prophylactically effective dose of apharmaceutical composition of a compound of Formula I.

Further exemplifying the invention is the method of treating obesity,diabetes, anxiety, depression, asthma, or hypertension, wherein thetherapeutically effective amount of the compound is about 1 to about 30mg/kg/day.

Still further exemplifying the invention is the method of inhibiting theonset of obesity, diabetes, anxiety, depression, asthma, orhypertension, wherein the prophylactically effective amount of thecompound is about 1 to about 30 mg/kg/day.

An additional illustration of the invention is a method of treating acondition selected from aggression, obsessive-compulsive disorders,hypertension, dysmenorrhea, congestive heart failure/cardiacinsufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis,renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis,water retention, nephrotic syndrome, central nervous injuries, obesity,anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memoryloss, sexual dysfunction, disorders of sleep and other circadianrhythms, and Cushing's disease. Preferably, the therapeuticallyeffective amount of the compound administered for treating any of theseconditions is about 1 to about 30 mg/kg/day.

Also included in the invention is the use of any of the compoundsdescribed above for the preparation of a medicament for treating acondition selected from aggression, obsessive-compulsive disorders,hypertension, dysmenorrhea, congestive heart failure/cardiacinsufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis,renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis,water retention, nephrotic syndrome, central nervous injuries, obesity,anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memoryloss, sexual dysfunction, disorders of sleep and other circadianrhythms, and Cushing's disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides nonpeptide substituted benzimidazol-2-onecompounds which are useful as antagonists of vasopressin and/ormodulators of Neuropeptide Y activity. Particularly, these compoundsinhibit the binding of vasopressin to V-1a, V-1b, and/or V-2 receptorsas well as the binding of Neuropeptide Y to the varied Neuropeptide Yreceptors. The compounds of this invention also inhibitvasopressin-induced intracellular calcium mobilization in transfectedHEK-293 cells expressing human V-1a or V-1b receptors and/or inhibitvasopressin-induced cAMP accumulation in transfected HEK-293 cellsexpressing human V-2 receptors.

More particularly, the present invention is directed to compounds ofFormula I:

wherein

A is aryl or heteroaryl having 0-4 heteroatoms selected from N, O, andS;

X is selected from S, O, NH, and NCN;

Y is S or O;

R₁ is 1-3 groups selected from hydrogen, alkyl, substituted alkyl,halogen, nitro, methylenedioxy, nitrile, —OR^(a), —NHR^(a),—NR^(a)R^(b), —S(O)_(p)R^(a), —N(R^(a))C(O)R^(b), —C(O)OR^(a),—C(O)NR^(a)R^(b), —SO₂NR^(a)R^(b), —N(R^(a))SO₂R^(b),N(R^(a))C(O)NR^(a), and NHCOOR^(a), wherein R^(a) and R^(b) areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl;

R₂ is selected from hydrogen, alkyl, and substituted alkyl;

R₃ is selected from hydrogen, alkyl, substituted alkyl, benzhydryl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, substituted heterocyclyl, —C(O)OR^(c), and—C(O)NR^(c)R^(d), wherein R^(c) and R^(d) are independently selectedfrom hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl, or NR^(c)R^(d) may be taken together to form a groupselected from heteroaryl, substituted heteroaryl, heterocyclyl, andsubstituted heterocyclyl;

R₄ and R₅ are independently selected from hydrogen, alkyl, alkylsubstituted with aryl or heteroaryl, phenyl, substituted phenyl, or R₄and R₅ are non-existent when n is 0;

p is from 0 to 2;

n is 0 or 1; and

m is 0 or 1, with the proviso that when m is 0, X is O, and R₃ isselected from heteroaryl, substituted heteroaryl, —C(O)OR^(c), and—C(O)NR^(c)R^(d) wherein R^(c) and R^(d) are independently selected fromalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, orNR^(c)R^(d) may be taken together to form a group selected fromheteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl, then n is 0;

or an optical isomer, enantiomer, diastereomer, racemate thereof, or apharmaceutically acceptable salt thereof.

The substituted benzimidazol-2-one compounds of the present inventionare vasopressin receptor antagonists. In a preferred embodiment, thecompounds are orally active. As demonstrated by the results of thepharmacological studies described hereinafter, the compounds show theability to block vasopressin binding to recombinant V-1a, V-1b, and/orV-2, and therefore are useful as therapeutics in or prophylacticsagainst conditions such as inner ear disorders, aggression,obsessive-compulsive disorders, hypertension, hyperglycemia,dysmenorrhea, congestive heart failure/cardiac insufficiency, coronaryvasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renalfailure, edema, ischemia, stroke, thrombosis, water retention, nephroticsyndrome, stress, and central nervous injuries.

The substituted benzimidazol-2-one compounds of the present inventionare also Neuropeptide Y receptor modulators. In a preferred embodiment,the compounds are orally active. The compounds show the ability tomodulate the binding of Neuropeptide Y to Neuropeptide Y receptors, andtherefore are useful as therapeutics in or prophylactics againstconditions such as obesity, anorexia, diabetes, hyperglycemia, anxiety,depression, asthma, memory loss, sexual dysfunction, and disorders ofsleep and other circadian rhythms.

In particular, compounds of Formula I, wherein A is phenyl orsubstituted phenyl are embodiments of the present invention. Compoundsof Formula I wherein X is S or N are further embodiments of the presentinvention.

Compounds of Formula I, wherein R₂ is alkyl substituted with one or moregroups selected from cycloalkyl, aryl, —NHC(NH)NR^(c)R^(d),—NR^(c)R^(d), —C(O)OR^(c), —OR^(c), —NHC(O)R^(c), and —C(O)NR^(c)R^(d),wherein R^(c) and R^(d) are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl, or NR^(c)R^(d)may be taken together to form a group selected from heteroaryl,substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, arealso embodiments of the present invention. More particularly X is S andR₃ is aryl or substituted aryl.

Compounds of Formula I, wherein A is aryl, X is S, R₂ is substitutedalkyl, m is 0, n is 1, R₃ and R₄ are both aryl, and R₅ is H, areparticular embodiments of the present invention.

More specifically, the following compounds are particular embodiments ofthe present invention:

1-piperidinecarbothioamide,4-[3-[3-(cyclohexylmethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[2,3-dihydro-2-oxo-3-[3-(1-piperidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-[3-(dimethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[2,3-dihydro-2-oxo-3-[3-(1-pyrrolidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-[3-[(aminoiminomethyl)amino]propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-[(4-chlorophenyl)phenylmethyl]-;

1-piperidinecarbothioamide,4-[3-(3-aminopropyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

1-piperidinecarbothioamide,4-[3-[2-(diethylamino)ethyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;

phenylalanine,N-[[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]carbonothioyl]-,methyl ester; and

1-piperidinecarbothioamide,4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-(1,2-diphenylethyl)-.

The compounds of Formula I may be prepared from readily availablestarting materials in accordance with various known synthetic routes.

The present invention is also directed to intermediates of Formulae 4and 5,

wherein P is hydrogen or a protecting group such as benzyl (Bn) or BOC(t-butyloxycarbonyl), i is an integer from 1 to 8, and A and R₁ are asdescribed hereinabove.

The compounds of the present invention may also be present in the formof a pharmaceutically acceptable salt or salts. For use in medicine, thesalt or salts of the compounds of this invention refer to non-toxic“pharmaceutically acceptable salt or salts.” Other salts may, however,be useful in the preparation of compounds according to this invention orof their pharmaceutically acceptable salts. Representative organic orinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representativebasic/cationic salts include, but are not limited to, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, orzinc.

Where the compounds according to this invention have at least onestereogenic center, they may accordingly exist as enantiomers. Where thecompounds possess two or more stereogenic centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

As used herein, “treating” a disorder means eliminating or otherwiseameliorating the cause and/or effects thereof. To “inhibit” or“inhibiting” the onset of a disorder means preventing, delaying orreducing the likelihood of such onset.

Methods are known in the art for determining therapeutically andprophylactically effective doses for the instant pharmaceuticalcomposition. The term “therapeutically effective amount” as used herein,means that amount of active compound or pharmaceutical agent thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. The term “prophylacticallyeffective amount” refers to that amount of active compound orpharmaceutical agent that inhibits in a subject the onset of a disorderas being sought by a researcher, veterinarian, medical doctor or otherclinician, the delaying of which disorder is mediated by the reductionof increased vascular resistance.

Unless otherwise noted, under standard nomenclature used throughout thisdisclosure the terminal portion of the designated side chain isdescribed first, followed by the adjacent functionality toward the pointof attachment.

Unless otherwise noted, “alkyl” as used herein, whether used alone or aspart of a substituent group, include straight and branched chains having1 to 8 carbon atoms, as well as cycloalkyl groups containing 3 to 8 ringcarbons and preferably 5 to 7 ring carbons, or any number within theseranges. For example, alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyland 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from thepreviously described straight or branched chain alkyl groups. An alkylas used herein may be substituted with one or more independent groupsincluding, for example, cycloalkyl, amino, substituted amino, halogen,hydroxy, heterocyclyl, substituted heterocyclyl, heteroaryl, substitutedheteroaryl, and/or unsubstituted or substituted aryl such as phenyl orbenzyl, —C(O)OR^(e), OR^(e), —OC(O)R^(e), —C(O)NR^(e)R^(f),—N(R^(e))C(O)R^(f), —N(R^(e))C(O)NR^(f), or —NHC(NH)NR^(e)R^(f) whereinR^(e) and R^(f) are independently selected from hydrogen, alkyl,halogen, hydroxy, heterocyclyl, substituted heterocyclyl, heteroaryl,substituted heteroaryl, and/or unsubstituted or substituted aryl.

“Heterocyclyl” or “heterocycle” is a 3- to 8-member saturated orpartially saturated single or fused ring system which consists of carbonatoms and from one to three heteroatoms selected from N, O and S. Theheterocyclyl group may be attached at any heteroatom or carbon atom,which results in the creation of a stable structure. Examples ofheterocyclyl groups include, but are not limited to morpholine,thiomorpholine, pyrazolidine, pyrazoline, pyrrolidine, piperidine, andpiperazine. “Heterocyclyl” or “heterocycle” may be substituted with oneor more independent groups including, but not limited to, H, halogen,oxo, OH, alkyl, substituted alkyl, amino, carboxyl, alkylcarboxyl, andalkoxy.

The term “Ar” or “aryl” as used herein, whether used alone or as part-ofa substituent group, refers to an aromatic group such as phenyl,naphthyl, and fluorenyl. When the Ar or aryl group is substituted, itmay have one to three substituents which are independently selected fromC₁-C₈ alkyl, substituted C₁-C₈ alkyl (e.g., trifluoromethyl), C₁-C₈alkoxy, substituted C₁-C₈ alkoxy (e.g., trifluoromethoxy), halogen,cyano, hydroxy, amino, substituted amino (e.g., C₁-C₄ alkylamino orC₁-C₄ dialkylamino wherein the alkyl groups can be the same ordifferent), nitro, carboxyl, and unsubstituted, mono-, di- ortri-substituted phenyl wherein the substituents on the phenyl areindependently selected from aryl, C₁-C₈ alkyl, C₁-C₈ alkoxy, substitutedC₁-C₈ alkyl, fluorinated C₁-C₈ alkoxy, halogen, cyano, hydroxy, amino,nitro, carboxyl, alkylcarboxyl, alkylamino, dialkylamino and heteroaryl.“Ph” or “PH” denotes phenyl. “Bn” denotes benzyl.

The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl,benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl,benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl,benzothiadiazolyl, benzotriazolyl or quinolinyl. Prefered heteroarylgroups include pyridinyl, thiophenyl, furanyl, quinolinyl, and

When the heteroaryl group is substituted, the heteroaryl group may haveone to three substituents which are independently selected from C₁-C₈alkyl, substituted C₁-C₈ alkyl, halogen, aryl, heteroaryl, alkoxy,alkylamino, dialkylamino, arylamino, nitro, carboxyl, alkylcarboxyl, andhydroxy.

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having 2 to 6 carbon atoms(branched or straight chain) derived from an organic acid by removal ofthe hydroxyl group.

The term “Ac” as used herein, whether used alone or as part of asubstituent group, means acetyl.

The term “halogen” shall include iodine, bromine, chlorine and fluorine.

Whenever the term “alkyl”, “acyl”, or “aryl” or either of their prefixroots appear in a name of a substituent (e.g., aralkyl, dialkylamino),it shall be interpreted as including those limitations given above for“alkyl”, “acyl”, and “aryl.” Designated numbers of carbon atoms (e.g.,C₁-C₆) shall refer independently to the number of carbon atoms in analkyl or cycloalkyl moiety or to the alkyl portion of a largersubstituent in which alkyl appears as its prefix root.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The present invention therefore provides a method of treating vascularresistance disorders in a subject in need thereof which comprisesadministering any of the compounds as defined herein in a quantityeffective to treat vascular resistance disorders. The compound may beadministered to a patient by any conventional route of administration,including, but not limited to, intravenous, oral, subcutaneous,intramuscular, intradermal and parenteral.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula I or salt thereof of the invention as theactive ingredient, is intimately admixed with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques, whichcarrier may take a wide variety of forms depending of the form ofpreparation desired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 1 mg to 30 mg/kgand may be given at a dosage of from about 1 to 30 mg/kg/day (preferred3 to 15 mg/kg/day). The dosages, however, may be varied depending uponthe requirement of the patients, the severity of the condition beingtreated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, sterile parenteral solutions orsuspensions, metered aerosol or liquid sprays, drops, ampoules,autoinjector devices or suppositories; for oral parenteral, intranasal,sublingual or rectal administration, or for administration by inhalationor insufflation. Alternatively, the composition may be presented in aform suitable for once-weekly or once-monthly administration; forexample, an insoluble salt of the active compound, such as the decanoatesalt, may be adapted to provide a depot preparation for intramuscularinjection. For preparing solid compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 0.1to about 500 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation. The compounds mayalso be resolved by formation of diastereomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using astereogenic HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

This invention will be better understood by reference to the schemes andexamples that follow, but those skilled in the art will readilyappreciate that these are only illustrative of the invention asdescribed more fully in the claims that follow thereafter.

In accordance with Scheme I, wherein P is hydrogen or a protecting groupsuch as benzyl (Bn) or BOC (t-butyloxycarbonyl), X′ is O or S, R_(2a) isselected from hydrogen, alkyl, and alkyl substituted with one or moregroups selected from cycloalkyl, halogen, hydroxy, heterocyclyl,substituted heterocyclyl, heteroaryl, substituted heteroaryl, andunsubstituted or substituted aryl, —C(O)OR^(e), OR^(e), —OC(O)R^(e),—C(O)NR^(e)R^(f), R_(2b) is selected from alkyl substituted with one ormore —N(R^(e))C(O)NR^(f), —NR^(e)C(O)R^(f), —NHC(NH)NR^(e)R^(f) or, i isan integer from 1 to 8, and A, m, n, R₁, R₂, R₃, R₄, R₅, R^(c), andR^(d) are as described hereinabove, benzimidazol-2-ones 2, can beprepared from diamines 1 (which, when A is aryl, may be made by knownmethods: e.g., J. Med. Chem. 30, 814-819 (1987)), using known conditionsand procedures. When A is heteroaryl, compound 1 can be prepared byreductive amination of the 2-nitro heteroarylamines that are known orcan be prepared using known procedures (e.g., Heterocycles 38, 529-540(1994), Arch. Pharm. 314, 564-567 (1981), JACS, 78, 242 (1956)) withcommercially available BOC or benzyl protected 4-piperdone followed byreduction of the nitro group under palladium catalyzed hydrogenationreaction conditions. The intermediate 2 can then be heated with analkyl, benzyl, or dialkylaminoalkyl halide in the presence of a basesuch as potassium carbonate, cesium carbonate or sodium hydride in asolvent such as dimethyl formamide (DMF), tetrahydrofuran (THF) oracetone to give the corresponding compounds of 3a. 2 can also be treatedwith a protected phthalimidoalkyl halide or a chloroalkyl halide to givethe corresponding compounds of 4 and 5a. The chloride of compound 4 canbe further displaced with mono- or di-substituted amines or cyclicamines to give the corresponding compounds of 6a.

The intermediates 3a, 5a, or 6a can be treated with trifluoroacetic acidto remove the protecting group P (P can be either benzyl or BOC) or withα-chloroethylchloroformate or under a hydrogenation condition to removea benzyl protecting group. This forms the intermediates 3b, 5b, or 6b,respectively. The piperidine nitrogen can then be substituted bytreatment with substituted isocyanates or substituted isothiocyanates inan appropriate solvent such as acetonitrile, tetrahydrofuran ormethylene chloride to give products Ia, Ib₁, and Ic, respectively,wherein Y is O. Compounds Ia, Ib₁ and Ic wherein Y is O can then beconverted to Ia, Ib₁ and Ic wherein Y is S by treatment with P₂S₅ with abase such as potassium hydroxide in an appropriate solvent such astoluene or benzene. In cases where the isocyanates or isothiocyanatesare not commercially available, they can be prepared by treating theappropriate amines with reagents such as phosgene, thiophosgene ordi-2-pyridylthionocabonate. Compound Ib₁ can be further treated withhydrazine in solvents such as ethanol (EtOH), methanol (MeOH), or THF togive the free amine Ib₂. The amine Ib₂ can then be acylated by theaddition of acylhalides or anhydrides to give compounds Id. Compound 3b,5b or 6b can be dissolved in an appropriate solvent such as DMF or THFthen heated in the presence of1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea to afford asubstituted guanidinyl intermediate 7. This intermediate 7, dissolved ina solvent such as DMF or THF, can be treated with alkyl or aryl halidesunder basic conditions (such as in NaH or KH) then treated withtrifluoroacetic acid to remove the BOC groups to give compounds Iewherein either m or n is 1, or R₃ is selected from hydrogen, alkyl,substituted alkyl, benzhydryl, heterocyclyl, substituted heterocyclyl,—C(O)OR^(c), and —C(O)NR^(c)R^(d).

In accordance with Scheme II, wherein Z is selected from aryl,substituted aryl, heteroaryl, and substituted heteroaryl, Z′ is

and A, Y, m, n, R₁, R₂, R₃, R₄, and R₅ are as described above, compoundsof formula If can be prepared by heating compound 3b, 5b, or 6b with theappropriate substituted isothiouronium salt 8 (prepared as described inJ. Med. Chem. 43, 2362-2370 (2000)) and triethylamine in a solvent suchas DMF, THF or acetonitrile. Compounds 3b, 5b, or 6b can also be addedto substituted thiourea 9, prepared by reacting sodium cyanamide withthe corresponding isothiocyanate, in the presence of a water solublecarbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and an appropriate solvent such as DMF and ethanol(procedure described in Tetrahedron Letters, 30, 7313-7316 (1989), toform corresponding compounds of Ig.

The method of treating conditions associated with vasopressin receptoror Neuropeptide Y receptor activity described in the present inventionmay be carried out using a pharmaceutical composition comprising any ofthe compounds as defined herein and a pharmaceutically acceptablecarrier. The pharmaceutical composition may contain between about 100 mgand 1000 mg, preferably about 100 to 500 mg, of the compound, and may beconstituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixers,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms can be in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methylcellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders of vascular resistance is required.

The daily dosage of the products may be varied over a wide range from100 to 3000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containingthe active ingredient in the amount sufficient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 1 mg/kg to about 30 mg/kg of body weight per day. Preferably, therange is from about 3 to about 15 mg/kg of body weight per day, mostpreferably, from about 5 to about 10 mg/kg of body weight per day. Thecompounds may be administered on a regimen of 1 to 2 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following examples are intended to illustrate the invention but notto limit it. Melting point determinations were done on a Thomas-Hoovercapillary melting point apparatus and are uncorrected. Nuclear magneticresonance (¹NMR) spectra were recorded on a Bruker AC300 (300 MHz)spectrometer. Chemical shifts are reported in parts per million (d)downfield relative to tetramethylsilane as standard. Mass spectra (m/z)were obtained on a HP 1100 LC/MSD.

EXAMPLE 1

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 1)

4-(2-Keto-1-benzimidazolinyl)piperidine (1.0 g, 4.61 mM) and benzhydrylisothiocyanate (1.0 g, 4.4 mM) in acetonitrile (20 ml) was stirred atroom temperature for 48 hours. The white solid precipitates werecollected and dried to give the product (1.78 g, 87%). m/z (MH⁺) 443

EXAMPLE 2

1-[(N1-Piperidinocarbothioyl-(2-(4-chlorophenyl)ethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 2)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-(4-chloropheny)ethyl isothiocyanate to give the product as a white solid (0.28 g, 86%).m.p. 234-236° C.

Anal: Calc'd for C21H23ClN4OS; C, 60.79; H, 5.59; N, 13.50. Found; C,60.83; H, 5.63; N, 13.33. m/z (MH⁺) 415

EXAMPLE 3

1-[(N1-Piperidinocarbothioylphenylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 3)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with phenylisothiocyanate to give the product as a white solid. m.p. 250-252° C.m/z (MH⁺) 353

EXAMPLE 4

1-[N1-Piperidinocarbothioyl-(2-methoxyphenyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 4)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-methoxyphenylisothiocyanate to give the product as a white solid. m.p. 196-199° C.m/z (MH⁺) 383

EXAMPLE 5

1-[(N1-Piperidinocarbothioyl-(4-methoxyphenyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 5)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 4-methoxyphenylisothiocyanate to give the product as a white solid. m.p. 238-243° C.m/z (MH⁺) 383

EXAMPLE 6

1-[(N1-Piperidinocarbothioyl-(3,4,5-trimethoxyphenyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 6)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with3,4,5-trimethoxyphenyl isothiocyanate to give the product as a whitesolid. m/z (MH⁺) 443.

EXAMPLE 7

1-[(N1-Piperidinocarbothioyl-(R)-(−)-1-(1-napthyl)ethylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 7)

4-(2-Keto-1-benzimidazolinyl)piperidine (0.11 g, 0.51 mM) and(R)-(−)-1-(1-naphthyl)ethyl isocyanate (0.099 g, 0.51 mM) inacetonitrile (5 ml) was stirred at room temperature overnight andevaporated in vacuo. The residual semi-solid was diluted with hexane.The solid precipitates were isolated by filtration and dried to give theproduct. m/z (MH⁺) 415

EXAMPLE 8

1-[(N1-Piperidinocarbothioylbenzoylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 8)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with benzoylisothiocyanate to give the product m/z (MH⁺) 381.

EXAMPLE 9

1-[N(Tert-butoxycarbonyl)piperidin-4yl]-1,3-dihydro-benzimidazol-2-one(Compound 9)

Di-tert-butyl dicarbonate (30 g, 0.14M) was slowly added to a cold (0°C.) solution of commercially available4-(2-keto-1-benzimidazolinyl)piperidine (30 g, 0.14M) in drytetrahydrofuran (250 ml). The mixture was slowly warmed up to roomtemperature and stirring was continued for 4 hours. Water (250 ml) wasslowly added and stirring was continued overnight. The THF was removedunder reduced pressure and the aqueous mixture extracted with ethylacetate (2×250 ml). The combined ethyl acetate (EtOAc) extracts werewashed with brine and dried over MgSO₄. The solvent was removed underreduced pressure to give the white solid product (42.2 g, 96%).

EXAMPLE 10

3-Methyl-1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 10)

Sodium hydride (0.06 g, 1.48 mM, 60% dispersion in mineral oil) wasadded to a mixture of compound 9 as prepared in Example 9 (0.41 g, 1.3mM) in dry THF (20 ml). The mixture was stirred at room temperature (RT)for one hour and methyl iodide (0.08 ml, 1.3 mM) was added. The mixturewas stirred at reflux for one hour, cooled to RT overnight and quenchedwith water (20 ml). The THF was removed under reduced pressure and theaqueous mixture extracted with ethyl acetate (2×25 ml). The combinedEtOAc extracts were dried over MgSO₄, evaporated in vacuo and residualsemi-solid diluted with methylene chloride (80 ml). The resultingsolution was cooled in an ice bath and excess trifluoroacetic acid (3ml) was added. The mixture was stirred at RT for 2½ hours and asaturated NaHCO₃ solution (80 ml) was slowly added. The layers wereseparated, the organic layer washed again with saturated NaHCO₃ (1×80ml) then dried over MgSO₄. The solvent was removed in vacuo and thesolid product (0.122 g, 0.52 mM) diluted with acetonitrile. Benzhydrylisothiocyanate was then added and the mixture stirred at RT overnight.The white solid precipitates were collected and dried to give theproduct. m/z (MH⁺) 457.

EXAMPLE 11

1-[(N1-Piperidinocarbothioylbenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 11)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with benzylisothiocyanate to give the product. m/z (MH⁺) 367.

EXAMPLE 12

1-[(N1-Piperidinocarbothioyl-2-chlorobenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 12)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-chlorobenzylisothiocyanate to give the product. m.p. 181-184° C. m/z (MH⁺) 401.

EXAMPLE 13

1-[(N1-Piperidinocarbothioyl-2,2-diphenylethylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 13)

Di(2-pyridyl) thionocarbonate (0.14 g, 0.61 mM) was added to a cold (0°C.) solution of 2,2-diphenylethylamine (0.12 g, 0.61 mM) in acetonitrile(10 ml). The mixture was slowly warmed up to room temperature, stirredat room temperature for 3 hours and4-(2-keto-1-benzimidazolinyl)piperidine (0.140 g 0.64 mM) was added. Theresulting solution was stirred at room temperature overnight, dilutedwith hexane (5 ml), stirred for an additional hour and filtered to givea solid product. m.p. 230-233° C. m/z (MH⁺) 457.

EXAMPLE 14

1-[(N1-Piperidinocarbothioyl-2-methoxybenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 14)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-methoxybenzylisothiocyanate to give the product. m/z (MH⁺) 397

EXAMPLE 15

1-[(N1-Piperidinocarbothioyl-(1-naphthalenemethyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 15)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with1-naphthalenemethyl isothiocyanate to give the product. m/z (MH⁺) 417

EXAMPLE 16

1-[(N1-Piperidinocarbothioyl-(3,4-methylenedioxybenzyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 16)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with3,4-methylenedioxybenzyl isothiocyanate to give the product. m/z (MH⁺)411

EXAMPLE 17

1-[(N1-Piperidinocarbothioyl-2,4-dichlorobenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 17)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2,4-dichlorobenzylisothiocyanate to give the product. m/z (MH⁺) 436

EXAMPLE 18

1-[(N1-Piperidinocarbothioyl-2,3-dimethoxybenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 18)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with2,3-dimethoxybenzyl isothiocyanate to give the product. m/z (MH⁺) 427

EXAMPLE 19

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(2-N-morpholinoethyl)-1,3-dihydro-benzimidazol-2-one(Compound 19)

Compound 9, prepared in Example 9, was treated as described in Example10 substituting methyl iodide with 4-(2-chloroethyl)morpholinehydrochloride (converted to the free base by washing a mixture of thehydrochloride salt in EtOAc with a saturated NaHCO₃ then drying overMgSO₄) to give the product. m/z (MH⁺) 556

EXAMPLE 20

1-[(N1-Piperidinocarbothioyl-3,4,5-trimethoxybenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 20)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with3,4,5-trimethoxybenzyl isothiocyanate to give the product. m/z (MH⁺) 457

EXAMPLE 21

1-[(N1-Piperidinocarbothioyl-(4-ethylbenzylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 21)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with 4-ethylbenzylamineto give the product. m/z (MH⁺) 409

EXAMPLE 22

1-[(N1-Piperidinocarbothioyl-2-phenethylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 22)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-phenethylisothiocyanate to give the product. m/z (MH⁺) 381

EXAMPLE 23

1-[(N1-Piperidinocarbothioyl-(2-(3-chlorophenyl)ethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 23)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with2-(3-chlorophenyl)ethyl isothiocyanate to give the product. m/z (MH⁺)415

EXAMPLE 24

1-[(N1-Piperidinocarbothioyl-(4-dimethyaminobenzylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 24)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with4-dimethylaminobenzylamine to give the product. m/z (MH⁺) 410

EXAMPLE 25

1-[(N1-Piperidinocarbothioyltriphenylmethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 25)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with tritylisothiocyanate to give the product. m/z (MH⁺) 519

EXAMPLE 26

1-[(N1-Piperidinocarbothioyl-(2-N-morpholinoethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 26)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-morpholinoethylisothiocyanate to give the product. m/z (MH⁺) 390

EXAMPLE 27

1-[(N1-Piperidinocarbothioyl-(4-fluoro-α-methylbenzylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 27)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with4-fluoro-α-methylbenyl isothiocyanate to give the product. m/z (MH⁺) 399

EXAMPLE 28

1-[(N1-Piperidinocarbothioyl-(4-chlorobenzylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 28)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 4-chlorobenzylisothiocyanate to give the product. m/z (MH⁺) 401

EXAMPLE 29

1-[(N1-Piperidinocarbothioyl-(3-pyridylmethylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 29)

A mixture of 4-(2-keto-1-benzimidazolinyl)piperidine (0.067 g, 0.308mM), 3-picolyl isothiocyanate hydrobromide (0.071 g, 0.308 mM) andtriethylamine (0.04 ml, 0.308) in acetonitrile (5 ml) were stirred at RTovernight. The resulting white solid precipitates were collected anddried to give the product. m/z (MH⁺) 368

EXAMPLE 30

1-[(N1-Piperidinocarbothioyl-1-methyl-2-(4-chlorophenyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 30)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with 4-chloroamphetaminehydrochloride to give the product. m/z (MH⁺) 429

EXAMPLE 31

1-[(N1-Piperidinocarbothioyl-2-(4-nitrophenethyl)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 31)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with4-nitrophenethylamine hydrochloride to give the product. m/z (MH⁺) 426

EXAMPLE 32

1-[(N1-Piperidinocarbothioyl-1,2-diphenylethylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 32)

4-(2-Kketo-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with 1,2-diphenethylamineto give the product. m/z (MH⁺) 457

EXAMPLE 33

1-[(N1-Piperidinocarbothioyl-9-aminofluoren-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 33)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with 9-aminofluorenehydrochloride to give the product. m/z (MH⁺) 441

EXAMPLE 34

1-[(N1-Piperidinocarbothioyl-4-chlorodiphenylmethylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 34)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with4-chlorobenzhydrylamine hydrochloride to give the product. m/z (MH⁺) 478

EXAMPLE 35

1-(N1-Piperidinocarbothioyldiphenylmethylamino-4-yl)-3-(2-diethyaminoethyl)-1,3-dihydrobenzimidazol-2-one(Compound 35)

Compound 9 as prepared in Example 9 was treated as described in Example10 substituting methyl iodide with N,N-diethylaminoethylchloride to givethe product. m/z (MH⁺) 317

EXAMPLE 36

1-(N1-Piperidinocarbothioyl-(4-fluoro-□-methylbenzylamino)-4-yl)-3-(2-diethyaminoethyl)-1,3-dihydrobenzimidazol-2-one(Compound 36)

Compound 9 as prepared in Example 9 was treated as described in Example35 substituting benzhydryl isothiocyanate with 4-fluoro-α-methylbenylisothiocyanate to give the product. m/z (MH⁺) 498.

EXAMPLE 37

1-(N1-Piperidinocarbothioyldiphenylmethylamino-4-yl)-3-benzyl-1,3-dihydrobenzimidazolbenzimidazol-2-one (Compound 37)

Compound 9 as prepared in Example 9 was treated as described in Example10 substituting methyl iodide with benzyl bromide to give the product.m/z (MH⁺) 533

EXAMPLE 38

1-[(N1-Piperidinocarbothioyl-2-phenpropylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 38)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-phenpropylisothiocyanate to give the product. m/z (MH⁺) 395

EXAMPLE 39

1-(N1-Piperidinocarbothioyl-2-(4-chlorophenyl)ethylamino-4-yl)-3-benzyl-1,3-dihydrobenzimidazol-2-one(Compound 39)

Compound 9 as prepared in Example 9 was treated as described in Example37 substituting benzhydryl isothiocyanate with 2-(4-chlorophenyl)ethylisothiocyanate to give the product. m/z (MH⁺) 506

EXAMPLE 40

1-[(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxymethyl)amino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 40)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with methylL-2-isothiocyanato-3-phenyl propionate to give the product. m/z (MH⁺)439

EXAMPLE 41

1-[(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxy)amino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 41)

A 6.6N NaOH (0.1 ml) solution was added to a mixture of Compound 40 (0.1g, 0.228 mM), prepared in Example 40, in methanol (20 ml). The reactionmixture was allowed to stir for five hours then acidified to pH of 2with concentrated hydrochloric acid. The methanol was removed underreduced pressure and the residual semi-solid diluted with water (10 ml).The mixture was stirred and the white solid precipitates collected byfiltration and dried to give the product (0.6 g, 62%). m/z (MH⁺) 425

EXAMPLE 42

1-(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxymethyl)amino-4-yl)-3-(2-diethyaminoethyl)-1,3-dihydrobenzimidazol-2-one(Compound 42)

Compound 9 as prepared in Example 9, was treated as described in Example35 substituting benzhydryl isothiocyanate with methylL-2-isothiocyanato-3-phenyl propionate to give the product. m/z (MH⁺)538

EXAMPLE 43

1-(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxy)amino-4-yl)-3-(2-diethyaminoethyl)-1,3-dihydrobenzimidazol-2-one(Compound 43)

A solution of Compound 42, prepared in Example 42, was treated asdescribed in Example 41 to give the product. m/z (MH⁺) 524

EXAMPLE 44

1-[(N1-Piperidinocarbothioyl-(2-phenyl-1-L-acetamidoethylcarbamoyl)amino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 44)

A mixture of Compound 41 (0.1 g, 0.24 mM) as prepared in Example 41,N-acetylethylenediamine (0.02 ml, 0.24 mM),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g,0.58) and 1-hydroxybenzotriazole hydrate (0.016 g, 0.12 mM) in DMF (20ml) was stirred at RT overnight and diluted with a 10% NaHCO₃ aqueoussolution (30 ml). The mixture was extracted with EtOAc (2×50 ml). Thecombined EtOAc extracts were dried over MgSO₄ and evaporated to dryness.The solid residue was diluted with EtOAc and allowed to stand at RTovernight. The solid precipitates were collected and dried to give theproduct (0.066 g, 55%).

m/z (MH⁺) 509

EXAMPLE 45

1-[(N1-Piperidinocarbothioyl-1-N-methylpiperazinocarbonyl-2-phenethylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 45)

Compound 41 as prepared in example 41, was treated as described inExample 44 substituting N-acetylethylenediamine with N-methylpiperazineto give the product. m/z (MH⁺) 507

EXAMPLE 46

1-[(N1-Piperidinocarbothioyl-1-[(tert-butoxycarbonyl)amino]-2-phenethylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 46)

Compound 41 as prepared in example 41, was treated as described inExample 44 substituting N-acetylethylenediamine with tert-butylN-(2-aminoethyl)carbamate to give the product. m/z (MH⁺) 567

EXAMPLE 47

1-[(N1-Piperidinocarbothioyl-(1-carbamoyl-2-phenylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 47)

Ammonium hydrogencarbonate (0.061 g, 0.77 mM) was added to a mixture ofCompound 41 (0.30 g, 0.70 mM), prepared in Example 41, BOC anhydride(0.17 g, 0.80 mM), and pyridine (0.1 ml) in dioxane (5 ml). Theresulting mixture was stirred at RT overnight and H₂O (30 ml) was added.The aqueous mixture was extracted with CH₂Cl₂ (2×30 ml). The combinedCH₂Cl₂ layers were washed with 1N HCl (1×60 ml) then dried over MgSO₄.The solvents were removed under reduced pressure and the crude oilpurified by chromatography (EM Silica gel 60, 5% MeOH in CH₂Cl₂) to givethe product. m/z (MH⁺) 424

EXAMPLE 48

1-[(N1-Piperidinocarbothioyl-2-methylphenylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 48)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-methylphenylisocyanate to give the product (0.16 g, 82%). m/z (MH⁺) 351

EXAMPLE 49

1-[(N1-Piperidinocarbothioyl-2-phenylphenylamino)-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 49)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 1 substituting benzhydryl isothiocyanate with 2-phenylphenylisocyanate to give the product (0.185 g, 55%). m/z (MH⁺) 413

EXAMPLE 50

1-[(N1-Piperidinocarbothioyl-D-tryptophancarboxymethylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 50)

Thiophosgene (0.04 ml, 0.51 mM) was added to a cold (0° C.) mixture ofD-tryptophan methyl ester hydrochloride (0.10 g, 0.39 mM) and pyridine(0.1 ml, 1.2 mM) in methylene chloride (20 ml). After stirring at 0° C.for an additional two hours, the 4-(2-keto-1-benzimidazolinyl)piperidine(0.085 g, 0.39 mM) was added and the mixture was allowed to stir at RTovernight. The mixture was then washed with H₂O (1×20 ml) and the CH₂Cl₂layer dried over MgSO₄. All solvents were evaporated in vacuo and theresidual oil chromatographed (EM silica gel 60; EtOAc) to give theproduct. m/z (MH⁺) 478

EXAMPLE 51

1-[(N1-Piperidinocarbothioyl-D-benzylcarboxymethylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 51)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 50 substituting D-tryptophan methyl ester hydrochloride withD-phenylalanine methyl ester hydrochloride to give the product. m/z(MH⁺) 439

EXAMPLE 52

1-[(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxymethyl)amino-4-yl]-3-(3-N-carbobenzyloxyamino)propyl-1,3-dihydrobenzimidazol-2-one(Compound 52)

To a cold (0° C.) mixture of bromopropylamine hydrobromide (3 g, 13.7mM) and triethylamine (5 ml, 35.9 mM) and methylene chloride (100 ml)was slowly added benzyl chloroformate (2.3 ml, 13.7 mM). The resultingmixture was slowly warmed up to RT, stirred at RT for 1 hour and H₂O(100 ml) was added. The layers were separated and the methylene chloridelayer dried over MgSO₄. The solvent was removed in vacuo to give an oil.The oil (300 mg, 1.1 mM) was diluted with acetone (50 ml), Compound 9(0.35 g, 1.1 mM) prepared in Example 9, and K₂CO₃ (0.3 g, 2.2 mM) wasadded. The mixture was stirred at reflux overnight, cooled to RT,evaporated in vacuo, and H₂O (50 ml) was added. The acetone was removedunder reduced pressure and the aqueous mixture extracted with EtOAc(2×60 ml). The combined EtOAc extracts were dried over MgSO₄ andevaporated in vacuo to give the Cbz protected intermediate (0.45 g,81%). The BOC group was removed by treatment of a cold (0° C.) solutionof the Cbz protected intermediate (0.45 g, 0.89 mM) in methylenechloride (20 ml) with excess trifluoroacetic acid (2 ml). The mixturewas stirred at room temperature overnight and evaporated to dryness.Trituration with diethyl ether gave the desired intermediate as a TFAsalt. This intermediate was substituted for4-(2-keto-1-benzimidazolinyl)piperidine and treated as described inExample 40 to give the product as a solid. m/z (MH⁺) 630.

EXAMPLE 53

1-(Piperdin-4-yl)-3-(3-phthalimidopropyl)benzimidazol-2-one (Compound53)

A mixture of Compound 9 (42.2 g, 0.13M), prepared in Example 9, andN-(3-bromopropyl)phthalimide (35 g, 0.13M) were dissolved in DMF (300ml). Cesium carbonate (100 g, 0.3M) was added in one portion and theresulting heterogenous mixture heated in an 80° C. oil bath for 16hours. The mixture was cooled to room temperature and the DMF removedunder reduced pressure. The residue was poured into ice water (800 ml)and stirred at room temperature overnight. The white solid precipitateswere collected and dried to give the desired product (60 g, 92%). TheBOC group was removed by treatment of a solution of the compound inmethylene chloride (500 ml) with excess trifluoroacetic acid (46 ml,0.6M). The mixture was stirred at room temperature overnight andevaporated to dryness under reduced pressure. The resulting white solidswere washed with diethyl ether and dried to give the desired TFA salt.m.p. 173-175° C. ¹H NMR (300 MHz, DMSO-d6) δ8.79 (m, 1H; 8.54 (m, 1H);7.82 (s, 4H); 7.35 (m, 1H); 7.25 (m, 1H); 7.07-6.90 (m, 2H); 4.55 (m,1H); 3.90 (t, J=7 Hz, 2H); 3.63 (t, J=7 Hz, 2H); 3.42 (m, 2H); 3.15 (m,2H); 2.60(m, 2H); 2.07 (m, 2H); 1.90 (m, 2H). MS: m/z (MH⁺) 405

EXAMPLE 54

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(3-N-phthalimidopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 54)

To a stirred mixture of Compound 53 (46 g, 0.087M), prepared in Example53, and triethylamine (20 ml, 0.177M in methylene chloride (500 ml) wasslowly added benzhydryl isothiocyanate (20 g, 0.087M). The mixture wasstirred at room temperature overnight and H₂O (100 ml) was added. TheCH₂Cl₂ was removed under reduced pressure and an additional 400 ml ofH₂O was added. The aqueous mixture was extracted with ethyl acetate(2×500 ml). The combined EtOAc extracts were dried (MgSO₄), filtered andevaporated in vacuo to give a semi-solid product. Recrystallization fromEtOH gave the product as a white solid (40 g, 71%). m/z (MH⁺) 630

EXAMPLE 55

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydrobenzimidazol-2-oneMonohydrochloride (Compound 57)

To a suspension of Compound 54 (22 g, 0.035M), prepared in Example 54,in EtOH (250 ml) was added anhydrous hydrazine (2 ml, 0.07M). Themixture was stirred at room temperature overnight and evaporated todryness. The solid residue was diluted with methylene chloride andfiltered to remove the phthalhydazide by-product. The supernatant wasevaporated in vacuo and flash column chromatographed (EM silica gel 60;10% MeOH in CH₂Cl₂) to give the product (12.2 g, 70%). m/z (MH⁺) 500.The HCl salt was prepared by the addition of a 1M HCl in Et₂O solutionto a mixture of the free base in methanol. The resulting white solidprecipitates were collected and dried to give the product (11 g, 85%).m.p. 189-190° C. ¹H NMR (300 MHz, DMSO-d6) □8.46(d, J=8.55 Hz, 1H); 7.96(s, 2H); 7.32 (m, 10H); 7.18-7.02 (m, 4H); 4.92 (d, J=12.9 Hz, 2H); 4.56(m, 1H); 3.92 (t, J=6.7 Hz, 2H); 3.16 (t, J=12.7 Hz, 2H); 2.82 (t, J=7.2Hz, 2H); 2.29 (m, 2H), 1.93 (m, 2H); 1.77 (m, 2H). Anal: Cal'd forC₂₉H₃₃N₅OS HCl 3/4H2O; C, 63.41; H,6.51; N,12.75. Found; C 63.42;H,6.32; N,12.61.

EXAMPLE 56

1-[(N1-Piperidinocarbothioyl-(1-L-carboxymethyl-2-phenylamino)-4-yl]-3-(3-phthalimidopropyl)-1,3-dihydro-benzimidazol-2-one(Compound 56)

Compound 53 as prepared in Example 53 was treated as described inExample 54 substituting benzhydryl isothiocyanate with methylL-2-isothiocyanato-3-phenyl propionate to the give the product. m/z(MH⁺) 626

EXAMPLE 57

1-[(N1-Piperidinocarbothioyl-(1-L-carboxymethyl-2-phenylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydrobenzimidazol-2-oneHydrochloride (Compound 57)

Compound 56, as prepared in Example 56, was treated as described inExample 55 to give the product. m/z (MH⁺) 533

EXAMPLE 58

1-[(N1-Piperidinocarbothioyl-(1-L-carboxymethyl-2-phenylamino)-4-yl]-3-(3-guanidinopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 58)

Compound 57 (0.167 g, 0.33 mM), as prepared in Example 57,3,5-dimethypyrazole-1-carboxamidine nitrate (0.067 g, 0.33 mM) andtriethylamine (0.09 ml, 0.66 mM) were combined in DMF (10 ml) andstirred in a 45° C. oil bath for 16 hr. The DMF was removed underreduced pressure and the-crude product triturated with Et₂O.Purification of the resulting semi-solid by column chromatography (EMSilica gel 60; 20% MeOH in CH₂Cl₂) afforded the product (0.040 g, 22%).m/z (MH⁺) 542

EXAMPLE 59

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(3-guanidinopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 59)

Compound 55, as prepared in Example 55, was substituted for compound 57and treated as described in Example 58 to the give the product. m/z(MH⁺) 575.

EXAMPLE 60

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(2-carboethoxyethyl)-1,3-dihydro-benzimidazol-2-one(Compound 60)

A mixture of Compound 9 (1.1 g, 3.5 mM), as prepared in Example 9, Ethyl3-bromopropionate (0.5 ml, 3.8 mM) and 2 equivalents of cesium carbonatein acetone was stirred at reflux for 48 hours. Once cooled to RT, H₂Owas added and the acetone was removed under reduced pressure. Theresulting aqueous mixture was extracted with EtOAc (2×60 ml). Thecombined EtOAc extracts were dried over MgSO₄ and evaporated in vacuo.The resulting semi-solid was diluted with methylene chloride (30 ml),cooled to 0° C. in an ice bath and treated with excess trifluoroaceticacid (3.0 ml). After stirring for 6 hours, saturated NaHCO₃ (60 ml) wasadded and the layers were separated. The aqueous layer was againextracted with CH₂Cl₂ (60 ml). The combined CH₂Cl₂ layers were driedover MgSO₄, and evaporated in vacuo to give a semi-solid. Thissemi-solid (0.8 g, 2.5 mM) was dissolved in acetonitrile (30 ml) andtreated with Benzhydryl isothiocyanate (0.6 g, 2.7 mM). The resultingmixture was stirred at RT overnight, evaporated in vacuo andchromatographed (EM silica gel 60; 10% EtOAc in CH₂Cl₂) to give theproduct. m/z (MH⁺) 543.

EXAMPLE 61

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(2-carboxyethyl)-1,3-dihydrobenzimidazol-2-one(Compound 61)

To a suspension of Compound 60 (0.110 g, 0.20 mM), as prepared inExample 60, in MeOH (10 ml) was added (0.15 ml) of a 50% NaOH/H₂Osolution. The suspension was stirred at RT till all solids dissolved (16hrs). The MeOH was removed under reduced pressure and a 1N HCl (20 ml)solution was added. The white solid precipitates were collected byfiltration, rinsing several times with water then dried to give theproduct (0.081 g, 79%). m/z (MH⁺) 543.

EXAMPLE 62

1-[(N1-Piperidinocarboyl-2-biphenylylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydro-benzimidazol-2-onehydrochloride (Compound 62)

Compound 53, as prepared in Example 53, was treated as described inExample 54 substituting benzhydryl isothiocyanate with2-biphenylylisocyanate. The resulting semi-solid product was substitutedfor Compound 54 then further treated as described in Example 55 to givethe product. m/z (MH⁺) 507.

EXAMPLE 63

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(2-aminoethyl)-1,3-dihydrobenzimidazol-2-oneHydrochloride (Compound 63)

Compound 9 (1.2 g, 3.77 mM), as prepared in Example 9, andN-(2-bromoethyl) phthalimide (0.9 g, 3.77 mM) were dissolved in DMF (20ml). Cesium carbonate (2.5 g, 7.5 mMM) was added in one portion and theresulting heterogenous mixture heated in an 80° C. oil bath for 16hours. The mixture was cooled to RT, and ice H₂O (60 ml) was added. Theaqueous mixture was extracted with two 80 ml portions of EtOAc. Thecombined EtOAc extracts were dried (MgSO₄) and evaporated in vacuo togive a solid intermediate. The BOC group was removed by treatment of amixture of the solid intermediate in methylene chloride (30 ml) withexcess trifluoroacetic acid (2 ml). The mixture was stirred at roomtemperature overnight, evaporated to dryness, diluted with EtOAc (80 ml)and washed with saturated NaHCO₃ (1×80 ml). The aqueous layer was againextracted with EtOAc (2×80 ml). The combined EtOAc extracts were driedover MgSO₄ and evaporated in vacuo to give the product (1.1 g, 75%).Without further purification, this product (0.40 g, 1.0 mM) was combinedwith benzhydryl isothiocyanate (0.23 g, 1.0 mM) in acetonitrile (30 ml).The mixture was stirred at RT overnight, evaporated in vacuo andchromatographed (EM silica gel 60, 10% EtOAc in CH₂Cl₂) to give asemi-solid product. Recrystallization from MeOH gave a white solidproduct. These solids (0.2 g) were dissolved in EtOH (15 ml) and treatedwith 2 equivalents of anhydrous hydrazine. The mixture was stirred atroom temperature overnight and evaporated to dryness. The solid residuewas diluted with methylene chloride and filtered to remove thephthalhydazide by-product. The supernatant was evaporated in vacuo andflash column chromatographed (EM silica gel 60; 10% MeOH in CH₂Cl₂) togive the product. The HCl salt was prepared by the addition of a 1M HClin Et₂O solution to a mixture of the free base in methanol. Theresulting white solid precipitates were collected and dried to give theproduct. m/z (MH⁺) 523.

EXAMPLE 64

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(4-aminobutyl)-1,3-dihydro-benzimidazol-2-one(Compound 64)

Compound 9, as prepared in Example 9, was treated as described inExample 63 substituting N-(2-bromoethyl) phthalimide withN-(4-bromobutyl) phthalimide to give the product. m/z (MH⁺) 551

EXAMPLE 65

1-[(N1-Piperidinocarbothioyl-4-chlorodiphenylmethylamino)-4-yl]-3-(4-aminobutyl)-1,3-dihydro-benzimidazol-2-one(Compound 65)

Di(2-pyridyl)thionocarbonate (0.46 g, 1.96 mM) was added to a cold (0°C.) solution of 4-chlorobenzhydrylamine hydrochloride (0.5 g, 1.96 mM)and triethylamine (0.2 ml, 1.96 mM) in methylene chloride (20 ml). Themixture was slowly warmed up to room temperature then stirred at roomtemperature overnight to form 4-chlorobenzhydryl isothiocyanate.Compound 9, prepared in Example 9, was treated as described in Example64 substituting the benzhydrylthioisocyanate with the 4-chlorobenzhydrylisothiocyanate prepared above to give the product. m/z (MH⁺) 585

EXAMPLE 66

1-[(N1-Piperidinocarbothioyl-1,1-di(p-anisyl)methylamino)-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 66)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 13 substituting 2,2-diphenylethylamine with1,1-di(p-anisyl)methylamine to give the product. m/z (MH⁺) 503.

EXAMPLE 67

5,6-Dichloro-1-[(N1-piperidinocarbothioylbenzhydrylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydro-benzimidazol-2-one(Compound 67)

A mixture of 1,2-dichloro-4-fluoro-5-nitrobenzene (5.5 g, 26.2 mM),4-amino-1-benzylpiperidine (4.98 g, 26.2 mM) and K₂CO₃ (7.23 g, 5.24 mM)in DMF (40 ml) was stirred in an 80° C. oil bath for 6 hours, cooled toRT overnight and H₂O (180 ml) was added. The aqueous mixture wasextracted with EtOAc (2×200 ml). The combined EtOAc extracts were washedwith brine, dried over MgSO₄, and evaporated in vacuo to give a darkoil. The oil was dissolved in EtOAc and 10% Pd/C (5 mole %) was added.The resulting mixture was hydrogenated in a Parr apparatus at 50 psi ofH₂ pressure over a 24 hour period. The mixture was filtered throughCelite and the filtrated evaporated in vacuo to give a crude diamineproduct. Triphosgene (4.2 g, 14 mM) was added to a mixture of thediamine (5 g, 14 mM) and triethylamine (2 ml, 14 mM) dissolved inmethylene chloride. The mixture was stirred at RT for 16 hours and thesolid precipitates collected by filtration and dried to give thedichloro substituted benzimidazolone product. This dichloro substitutedbenzimidazolone (5.5 g, 15.7 mM), N-(3-Bromopropyl)phthalimide (3.9 g,15.7 mM) and cesium carbonate (9.85 g, 30 mM) in DMF (50 ml) werestirred in an 80-85° C. oil bath for 48 hours, cooled to RT andevaporated in vacuo to remove the DMF. The residue was diluted with H₂O(100 ml) and extract with EtOAc (2×100 ml). The combined EtOAc extractswere dried over MgSO₄, and evaporated in vacuo to give a crude mixturecontaining the product. Recrystallization from Et₂O gave an off-whitesolid product. m/z (MH⁺) 562.

The off-white solids (0.32 g, 0.57 mM) were dissolved in methylenechloride (20 ml), cooled in an ice-bath to 0° C., and 1-chloroethylchloroformate (0.08 ml, 0.74 mM) was slowly added. The mixture wasstirred at 0° C. for one hour, evaporated in vacuo and methanol (30 ml)was added Following 2 hours of refluxing, the mixture was cooled, wasevaporated in vacuo, diluted with methylene chloride and stirred at RTfor 1 hour. The solid precipitates were collected and dried to providethe de-benzylated intermediate as the HCl salt m/z (MH⁺) 472. Benzhydrylisothiocyanate (0.60 g, 0.26 mM) was then added to a mixture of thede-benzylated intermediate (0.134 g, 0.26 mM) and triethylamine (0.04ml, 0.26 mM) in methylene chloride (20 ml). The resulting mixture wasstirred at RT overnight, diluted with water (15 ml) and layers wereseparated. The aqueous layer was again extracted with methylene chloride(20 ml). The combined methylene chloride extracts were dried over MgSO₄,evaporated in vacuo, dissolved in EtOH (15 ml) then treated with 2equivalents of anhydrous hydrazine. The mixture was stirred at roomtemperature overnight and evaporated to dryness. The solid residue wasdiluted with methylene chloride and filtered to remove thephthalhydazide by-product. The supernatant was evaporated in vacuo andflash column chromatographed (EM silica gel 60; 10% MeOH in CH₂Cl₂) togive the product. m/z (MH⁺) 568

EXAMPLE 68

1-[(N1-Piperidinocarbothioyl-1,1-di(p-anisyl)methylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydrobenzimidazol-2-oneHydrochloride (Compound 68)

Di(2-pyridyl)thionocarbonate (0.286 g, 1.2 mM) was added to a cold (0°C.) solution of 1,1-di(p-anisyl)methyl amine (0.3 g, 1.2 mM) andtriethylamine (0.17 ml) in methylene chloride (10 ml). The resultingmixture was slowly warmed up to RT over a 4 hour period then stirred atRT for additional 1 hour to provide the 1,1-di(p-anisyl)methylisothiocyanate. The prepared isothiocyanate was added to Compound 53(0.94 g, 0.43 mM), prepared in Example 53, dissolved in methylenechloride (10 ml). The mixture was stirred at RT overnight, diluted withwater (20 ml) and the layers were separated. The aqueous layer was againextracted with methylene chloride (2×20 ml). The combined CH₂Cl₂extracts were dried over MgSO₄, evaporated in vacuo and chromatoraphed(EM silica gel 60, 10% EtOAc in CH₂Cl₂) to give the pthalimideintermediate. This intermediate, substituted for Compound 54, wastreated as described in Example 55 to give the HCl salt of the product.m/z (MH⁺) 560

EXAMPLE 69

1-[(N1-piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(2-amidoethyl)-1,3-dihydro-benzimidazol-2-one(Compound 69)

Ammonium hydrogencarbonate (0.014 g, 0.178 mM) was added to a mixture ofCompound 61 (0.046 g, 0.089 mM), prepared in Example 61, di-tert-butyldicarbonate (0.020 g, 0.089 mM), and pyridine (0.1 ml) dissolved indioxane (4 ml). The mixture was stirred at RT overnight and water (50ml) was added. The mixture was stirred at RT for an additional 4 hoursand the solid precipitates collected and dried to give a white solidproduct. m/z (MH⁺) 514.

EXAMPLE 70

1-[N-(Tert-butoxycarbonyl)piperidin-4yl]-3-(3-chloropropyl)-1,3-dihydrobenzimidazol-2-one(Compound 70)

A mixture of Compound 9 (1.7 g, 5.3 mM), as prepared in Example 9,bromopropylchloride (5.3 ml, 5.3 mM) and cesium carbonate (3.5 g, 10.6mM) in acetone (60 ml) was stirred at reflux for 24 hours then cooled toRT. The acetone was removed under reduced pressure, the residue dilutedwith water (60 ml) and the aqueous mixture was extracted with ethylacetate (2×60 ml). The combined ethyl acetate layers were dried overMgSO₄ and evaporated in vacuo to give the product (2.1 g, 100%) as anoil that solidified on standing. m/z (MH⁺) 393.

EXAMPLE 71

1-[(N1-piperidinocarbothioylbenzhydrylamino)-4-yl]-3-(3-N,N-dimethylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 71)

Compound 70 (0.490 g, 1.25 mM), prepared in Example 70, excessdimethylamine (2 ml, 40% aqueous solution) and THF (20 ml) were combinedin a sealed tube and heated in a 68° C. oil bath for 24 hours. Themixture was allowed to cool to room temperature and the THF removedunder reduced pressure. Water (30 ml) was added and the resultingaqueous mixture extracted with EtOAc (2×30 ml). The combined EtOAcextracts were dried over MgSO₄ and evaporated in vacuo to give asemi-solid. m/z (MH⁺) 403. The BOC group was removed by treatment of asolution of the semi-solid in methylene chloride (10 ml) with excesstrifluoroacetic acid (1 ml). The mixture was stirred at room temperatureovernight and evaporated in vacuo. The residue was diluted with EtOAc(80 ml) then washed with saturated NaHCO₃ (2×60 ml). The EtOAc extractwas dried over MgSO₄, evaporated in vacuo and the residual semi-solid(0.332 g, 0.011 mM) dissoloved in methylene chloride (40 ml) was treatedwith one equivalent of benzhydryl isothiocyanate (0.25 g, 0.011 mM). Theresulting mixture was stirred at RT overnight, evaporated in vacuo anddiluted with EtOAc. The precipitates were collected and dried to givethe white solid product. m/z (MH⁺) 528.

EXAMPLE 72

1-(Piperidino-4-yl)-3-(3-N-pyrrolidinopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 72)

A mixture of Compound 70 (2.26 g, 5.7 mM), prepared in Example 70,pyrrolidine (1.0 ml, 10.4 mM), potassium carbonate (1.6 g, 11.5 mM) anda catalytic amount of sodium iodide in DMF (40 ml) was heated in a 70°C. oil bath for 16 hours. The mixture was allowed to cool to RT thendiluted with water (200 ml). The aqueous mixture was extracted withEtOAc (2×250 ml). The combined EtOAc extracts were dried over MgSO₄ andevaporated in vacuo to give the product as an oil (2.4 g, 100%). Thisoil was dissolved in methylene chloride (100 ml), cooled in an ice bathto 0° C. and trifluoroacetic acid (10 ml) was slowly added. The mixturewas slowly warmed to RT and stirred for 6 hours. The solvent and excessTFA was removed under reduced pressure and the product triturated withEt₂O to give the white solid product as the trifloroacetic acid (TFA)salt (2.82 g, 89%). m/z (MH⁺) 327.

EXAMPLE 73

1-[(N1-piperidinocarbothioylbenzhydrylamino)-4-yl]-3-(3-N-pyrrolidinopropyl)-1,3-dihydro-benzimidazol-2-one(Compound 73)

Compound 72, prepared in Example 72, was diluted with EtOAc (50 ml) andwashed with saturated NaHCO₃ (50 ml). The aqueous layer was againextracted with EtOAc (60 ml). The combined EtOAc extracts were driedover MgSO₄ and evaporated in vacuo to give the free base of Compound 72.A mixture of this free base (0.132 g, 0.40 mM) and benzhydrylisothiocyanate (0.091 g, 0.40 mM) in methylene chloride (20 ml) werestirred at RT overnight. The methylene chloride was removed underreduced pressure and the residue diluted with EtOAc. The precipitateswere collected and dried to give the white solid product. m/z (MH⁺) 554.

EXAMPLE 74

1-[(N1-Piperidinocarbonylbenzylamino-4-yl]-1,3-dihydro-benzimidazol-2-one(Compound 74)

A mixture of 4-(2-keto-1-benzimidazolinyl)piperidine (0.11 g, 0.51 mM)and benzyl isocyanate (0.068 g, 0.53 mM) in methylene chloride (10 ml)were stirred at RT overnight and filtered to give the white solidproduct. m/z (MH⁺) 351.

EXAMPLE 75

1-[(N1-Piperidinocarbonyldiphenylmethylamino-4-yl]-1,3-dihydrobenzimidazol-2-one(Compound 75)

4-(2-Keto-1-benzimidazolinyl)piperidine was treated as described inExample 74 substituting benzyl isocyanate with benzhydryl isocyanate togive the white solid product. m/z (MH⁺) 427

EXAMPLE 76

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(3-acetamidopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 76)

One drop of sulfuric acid was added to a mixture of the free base ofCompound 55 (0.286 g, 0.57 mM), as prepared in Example 55, dissolved inacetic anhydride (20 ml). The mixture was stirred at room temperaturefor 4 hours and poured into ice water (80 ml). The resulting aqueousmixture was extracted the EtOAc (2×80 ml). The combined EtOAc extractswere washed with 0.5N NaOH solution (80 ml), dried over MgSO₄ andevaporated in vacuo to give a crude semi-solid. Purification by columnchromatography produced an off-white solid product. m/z (MH⁺) 542.

EXAMPLE 77

1-[(N1-Piperidinocarbonyldiphenylmethylamino)-4-yl]-3-(3-aminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 77)

Compound 9, as prepared in Example 9, was treated as described inExample 63 substituting N-(2-bromoethyl) phthalimide withN-(3-bromopropyl) phthalimide and benzhydryl isothiocyanate withbenzhydryl isocyanate to give the white solid product (0.18 g, 65%). m/z(MH⁺) 484.

EXAMPLE 78

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N-(N-Methylpiperazino)propyl)-1,3-dihydrobenzimidazol-2-one(Compound 78)

A mixture of Compound 70 (0.150 g, 0.38 mM), as prepared in Example 70,N-methylpiperazine (0.05 ml, 0.45 mM), potassium carbonate (0.08 g, 0.57mM) and a catalytic amount of sodium iodide in DMF (10 ml) was heated ina 70° C. oil bath for 16 hours. The mixture was allowed to cool to RTthen diluted with water (30 ml). The aqueous mixture was extracted withEtOAc (2×40 ml). The combined EtOAc extracts were dried over MgSO₄ andevaporated in vacuo to give an oil (167 mg, 95%). This oil was dissolvedin methylene chloride (20 ml), cooled in an ice bath to 0° C. andtrifluoroacetic acid (2 ml) was slowly added. The mixture was slowlywarmed to RT and stirred for 6 hours. The solvent and excess TFA wasremoved under reduced pressure and the product triturated with Et₂O togive the white solid as the TFA salt. This white solid (0.150 g, 0.26mM) was combined with triethylamine (0.09 ml, 0.64 mM) and benzhydrylisothiocyanate (0.058 g, 0.26 mM) in CH₂Cl₂ and stirred at roomtemperature for 16 hours. The reaction mixture was diluted with waterand layers were separated. The aqueous layer was again extracted withCH₂Cl₂. The combined CH₂Cl₂ layers were dried over MgSO4, evaporated invacuo and filtered through a short silica gel column (EM Silica gel 60;5% MeOH in CH₂Cl₂) to give the product as a solid. (86 mg, 57%). m/z(MH⁺) 583.

EXAMPLE 79

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N,N-dipropylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 79)

Compound 70, prepared in Example 70, was treated as described in Example78 substituting the N-methylpiperazine with dipropylamine to give theproduct as a solid. m/z (MH⁺) 584

EXAMPLE 80

1-[(N1-piperidinocarbonylbiphenylmethylamino)-4-yl]-3-(3-N,N-dipropylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 80)

Compound 70, prepared in Example 70, was treated as described in Example79 substituting the substituting the benzhydryl isothiocyanate withbenzhydryl isocyanate to give the product as a solid. m/z (MH⁺) 568.

EXAMPLE 81

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 81)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with piperdine to givethe product as a solid. m/z (MH⁺) 568

EXAMPLE 82

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3,4-dimethylpiperidine-1-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 82)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with 3,5-methylpiperidineto give the product as a solid. m/z (MH⁺) 596

EXAMPLE 83

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-[3-(4-ethylcarboxypiperidine)propyl]-1,3-dihydrobenzimidazol-2-one(Compound 83)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with4-ethylcarboxypiperidine to give the product as a solid. m/z (MH⁺) 640

EXAMPLE 84

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-morpholinopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 84)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with morpholine to givethe product as a solid. m/z (MH⁺) 570.

EXAMPLE 85

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N,N-diethylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 85)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with diethylamine to givethe product as a solid. m/z (MH⁺) 556

EXAMPLE 86

1-[(N1-Piperidinocarbothioyl-(2-phenyl-1-L-carboxymethyl)amino-4-yl)-4-yl]-3-(3-pyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 86)

A mixture of Compound 72 (0.26 g, 0.47 mM), as prepared in example 72,triethylamine (0.2 ml, 1.4 mM) and methyl L-2-isothiocyanato-3-phenylpropionate (0.104 g, 0.47 mM) in methylene chloride (30 ml) were stirredat RT overnight, diluted with water (30 ml) and layers were separated.The aqueous layer was again extracted with CH₂Cl₂ (1×30 ml). Thecombined CH₂Cl₂ layers were dried over MgSO₄, evaporated in vacuo thenfiltered through a short silica gel column (EM Silica gel 60; 5% MeOH inCH₂Cl₂) to give the product as a solid. m/z (MH⁺) 550

EXAMPLE 87

1-[(N1-Piperidinocarbothioyl-(2-methoxyphenyl)amino)-4-yl]-3-(3-pyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 87)

Compound 72, as prepared in Example 72, was treated as described inExample 86 substituting methyl L-2-isothiocyanato-3-phenyl propionatewith 2-methoxyphenyl isothiocyanate to give a solid product. m/z (MH⁺)494

EXAMPLE 88

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-cyclohexylmethylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 88)

To a mixture of the free base of Compound 55 (0.050 g, 0.1 mM), preparedin Example 55, and cyclohexanecarboxaldehyde (0.012 g, 0.1 mM) inmethanol (10 ml) was added acetic acid (3 drops). The resultant mixturewas stirred at RT for 3 hours and sodium cyanoborohydride (0.006 g, 0.1mM) was added. The mixture was stirred at RT for two hours, cooled in anice bath and a 6N NaOH solution was added to a basic pH. Water (50 ml)was added and the resulting mixture extracted with ethyl acetate (2×60ml). The combined EtOAc extracts were dried over MgSO4, evaporated invacuo and purified by chromatography (EM silica gel 60; 5% MeOH inCH₂Cl₂) to give the product as a white solid. m/z (MH⁺) 596

EXAMPLE 89

1-[(N1-Piperidinocarbothioyl-(2-fluorobenzyl)amino)-4-yl]-3-(3-pyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 89)

Compound 72, as prepared in Example 72, was treated as described inExample 86 substituting methyl L-2-isothiocyanato-3-phenyl propionatewith 2-fluorobenzyl isothiocyanate to give the product as a solid. m/z(MH⁺) 480.

EXAMPLE 90

1-(N1-Piperidinocarbothioyl-(2-phenylbenzylamino)-4-yl)-3-(2-diethyaminoethyl)benzimidazol-2-one(Compound 90)

Compound 9, as prepared in Example 9 was treated as described in Example35 substituting the benzhydryl isothiocyanate with 2-phenylbenzylisothiocyanate (prepared by treating 2-phenylbenzylamine withdi(2-pyridyl)thionocarbonate following the procedure used to prepare1,1-di(p-anisyl)methyl isothiocyanate in Example 68) to give the productas a solid. m/z (MH⁺) 542

EXAMPLE 91

1-(N1-Piperidinocarbonyldiphenylmethylamino-4-yl)-3-(2-N,N-diethyaminoethyl)benzimidazol-2-one(Compound 91)

Compound 9, as prepared in Example 9, was treated as described inExample 35 substituting benzhydryl isothiocyanate with benzhydrylisocyanate to give the product as a solid. m/z (MH⁺) 526.

EXAMPLE 92

1-[(N1-Piperidinocarbonyl-2-methylphenylamino)-4-yl]-3-(2-N,Ndiethylaminoethyl)-1,3-dihydrobenzimidazol-2-one(Compound 92)

Compound 9, as prepared in Example 9, was treated as described inExample 35 substituting benzhydryl isothiocyanate with 2-methylphenylisocyanate to give the product as a solid. m/z (MH⁺) 450

EXAMPLE 93

1-(N1-Piperidinocarbothioyldiphenylmethylamino-4-yl)-3-(3-1N-methylpyrrolidin-2-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 93)

Compound 9, as prepared in Example 9, was treated as described inExample 10 substituting methyl iodide with2-2-(chloroethyl)-1-methylpyrrolidine hydrochloride (converted to thefree base by washing a mixture of the hydrochloride salt in EtOAc with asaturated NaHCO₃ solution then drying over MgSO₄) to give the product.m/z (MH⁺) 538.

EXAMPLE 94

1-(N1-Piperidinocarbonyldiphenylmethylamino-4-yl)-3-(3-1N-methylpyrrolidin-2-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 94)

Compound 9, as prepared in Example 9, was treated as described inExample 93 substituting the benzhydryl isothiocyanate with benzhydrylisocyanate to give the product.

EXAMPLE 95

1-[(N1-piperidinocarbonylbiphenylmethylamino)-4-yl]-3-(3-morpholinopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 95)

Compound 70, as prepared in Example 70, was treated as described inExample 84 substituting the benzhydryl isothiocyanate with benzhydrylisocyanate to give the product as a solid. m/z (MH⁺) 554.

EXAMPLE 96

1-[(N1-piperidinocarbonyldiphenylmethylamino)-4-yl]-3-(3-N-pyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 96)

Compound 72, prepared in Example 72, was treated as described in Example86 substituting methyl L-2-isothiocyanato-3-phenyl propionate withbenzhydryl isocyanate to give the product as a solid. m/z (MH⁺) 538.

EXAMPLE 97

1-[(N1-piperidinocarbonylbiphenylmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 97)

Compound 72, prepared in Example 72, was treated as described in Example81 substituting the benzhydryl isothiocyanate with benzhydryl isocanateto give the product as a solid. m/z (MH⁺) 552.

EXAMPLE 98

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N,N-methylcyclohexylaminopropyl)-1,3-dihydrobenzimidazol-2-one(Compound 98)

Compound 70, prepared in Example 70, was treated as described in Example78 substituting the N-methyl piperazine with N-methyl cyclohexylamine togive the solid as a product. m/z (MH⁺) 596.

EXAMPLE 99

1-[(N1-piperidinocarbonylbiphenylmethylamino)-4-yl]-3-(4-methylpiperidin-1-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 99)

Compound 70, prepared as described in Example 70, was treated asdescribed in Example 113 substituting the benzhydryl isothiocyanate withbenzhydryl isocyanate to give the title compound. m/z (MH⁺) 566.

EXAMPLE 100

1-[(N1-piperidinocarbonylbiphenylmethylamino)-4-yl]-3-(3-N-(N-Methylpiperazino)propyl)-1,3-dihydrobenzimidazol-2-one(Compound 100)

Compound 70, prepared as described in Example 70, was treated asdescribed in Example 78 substituting the benzhydryl isothiocyanate withbenzhydryl isocyanate to give the title compound. m/z (MH⁺) 567.

EXAMPLE 101

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3,4-dimethypiperidin-1-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 101)

Compound 70, prepared as described in Example 70, was treated asdescribed in Example 82 substituting the benzhydryl isothiocyanate withbenzhydryl isocyanate to give the title compound. m/z (MH⁺) 580.

EXAMPLE 102

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(N-dihydropyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 102)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with 3-pyrroline and thebenzhydryl isothiocyanate with benzhydryl isocyanate to give the titlecompound. m/z (MH⁺) 536.

EXAMPLE 103

1-[N-(Tert-butoxycarbonyl)piperidin-4yl]-3-(3-chloropropyl)-1,3-dihydro-benzimidazol-2-one(Compound 103)

The title compound was prepared as described in Example 70 substitutingthe 3-bromopropylchloride with 4-bromobutylchloride. m/z (MH⁺) 407.

EXAMPLE 104

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N-pyrrolidinylbutyl)-1,3-dihydrobenzimidazol-2-one(Compound 104)

A mixture of Compound 103 (0.280 g, 0.69 mM), as prepared in Example103, pyrrolidine (0.08 ml, 0.96 mM), potassium carbonate (0.190 g, 1.4mM) and a catalytic amount of sodium iodide in DMF (10 ml) was heated ina 70° C. oil bath for 16 hours. The mixture was allowed to cool to RTthen diluted with water (200 ml). The aqueous mixture was extracted withEtOAc (2×250 ml). The combined EtOAc extracts were dried over MgSO₄ andevaporated in vacuo to give an oil. This oil was dissolved in methylenechloride (20 ml), cooled in an ice bath to 0° C. and trifluoroaceticacid (2 ml) was slowly added. The mixture was stirred at 0° C. for 3½hours. The solvent and excess TFA was removed under reduced pressure andthe product triturated with Et₂O to give a semi-solid intermediate asthe TFA salt (0.35 g, 89%). This intermediate (0.350 g, 0.61 mM) wascombined with triethylamine (0.2 ml, 1.5 mM) and benzhydrylisothiocyanate (0.138 g, 0.61 mM) in CH₂Cl₂ (40 ml) and stirred at roomtemperature for 16 hours. The reaction mixture was diluted with water(40 ml) and layers were separated. The aqueous layer was again extractedwith CH₂Cl₂ (40 ml). The combined CH₂Cl₂ layers were dried over MgSO₄,evaporated in vacuo and the crude semi-solid purified by chromatography(EM Silica gel 60; 5% MeOH in CH₂Cl₂) to give the product (86 mg, 57%).m/z (MH⁺) 568.

EXAMPLE 105

1-[(N1-piperidinocarbothioylbenzylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 105)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with benzylisothiocyanate to give the product as a solid. m/z (MH⁺) 492.

EXAMPLE 106

1-[(N1-piperidinocarbonybenzylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 106)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with benzyl isocyanateto give the product as a solid. m/z (MH⁺) 476

EXAMPLE 107

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-N-pyrrolidinylbutyl)-1,3-dihydrobenzimidazol-2-one(Compound 107)

Compound 103, as prepared in Example 103, was treated as described inExample 104 substituting pyrrolidine with piperidine to give the productas a solid. m/z (MH⁺) 582.

EXAMPLE 108

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(3-hydroxypropyl)-1,3-dihydrobenzimidazol-2-one(Compound 108)

Compound 9, as prepared in Example 9, was treated as described inExample 53 substituting the N-(3-bromopropy)phthalimide with2-(3-bromopropoxy)tetrahydro-2H-pyran. The resulting TFA salt wasfurther treated as described in Example 54 to give the product. m/z(MH⁺) 501.

EXAMPLE 109

1-[(N1-piperidinocarbothioyl-2-methylphenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 109)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-methylphenylisothiocyanate to give the product as a solid. m/z (MH⁺) 492.

EXAMPLE 110

1-[(N1-piperidinocarbonyl-2-methylphenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 110)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-methylphenylisocyanate to give the product as a solid. m/z (MH⁺) 476

EXAMPLE 111

1-[(N1-piperidinocarbothioyl-2-methoxybenzylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 111)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-methoxybenzylisothiocyanate to give the product as a solid. m/z (MH⁺) 522.

EXAMPLE 112

1-[(N1-piperidinocarbothioyl-1-naphthalmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 112)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with1-Naphthalenemethyl isothiocyanate to give the product as a solid. m/z(MH⁺) 542.

EXAMPLE 113

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(4-methylpiperidin-1-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 113)

Compound 70, as prepared in Example 70, was treated as described inExample 78 substituting the N-methylpiperazine with 4-methylpiperidineto give the product as a solid. m/z (MH⁺) 582.

EXAMPLE 114

1-[(N1-piperidinocarbonyl-2-fluorophenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 114)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-fluorophenylisocyanate to give the product as a solid. m/z (MH⁺) 480.

EXAMPLE 115

1-[(N1-piperidinocarbonthioyl-2-fluorophenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 115)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-fluorophenylisothiocyanate to give the product as a solid. m/z (MH⁺) 496.

EXAMPLE 116

1-[(N1-piperidinocarbonthioyl-R-(−)-alpha-methylbenzylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 116)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate withR-(−)-alpha-methylbenzyl isothiocyanate to give the product as a solid.m/z (MH⁺) 506.

EXAMPLE 117

1-[(N1-piperidinocarbonyl-2-propylphenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 117)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-propylphenylisocyanate to give the product as a solid. m/z (MH⁺) 504.

EXAMPLE 118

1-[(N1-piperidinocarbothioyl-2,2-diphenylethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 118)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2,2-diphenylethylisothiocyanate to give the product as a solid. m/z (MH⁺) 582.

EXAMPLE 119

1-[(N1-piperidinocarbothioyl-2-methoxyphenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 119)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-methoxyphenylisothiocyanate to give the product as a solid. m/z (MH⁺) 508.

EXAMPLE 120

1-[(N1-piperidinocarbonyltriphenylmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 120)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with trityl isocyanateto give the product as a solid. m/z (MH⁺) 628.

EXAMPLE 121

1-[(N1-piperidinocarbothioyltriphenylmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-5-trifluoromethyl-1,3-dihydrobenzimidazol-2-one(Compound 121)

4-Fluoro-3-nitrobenzotrifluoride was substituted for1,2-dichloro-4-fluoro-5-nitrobenzene and treated as described in Example67, also substituting the N-(3-bromopropyl)phthalimide forN-(gammachloropropyl)piperidine HCl, to give the product. m/z (MH⁺) 636.

EXAMPLE 122

1-[(N1-piperidinocarbothioylbiphenylmethylamino)-4-yl]-3-(4-propylpiperidin-1-yl-propyl)-1,3-dihydrobenzimidazol-2-one(Compound 122)

Compound 70, prepared in Example 70, was treated as described in Example78 substituting the N-methyl piperazine with 4-N-propylpiperidine togive the solid as a product. m/z (MH⁺) 610.

EXAMPLE 123

1-[(N1-Piperidinocarbothioyl-(2,3-dimethoxybenzyl)amino)-4-yl]-3-(3-pyrrolidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 123)

Compound 72, as prepared in Example 72, was treated as described inExample 86 substituting methyl L-2-isothiocyanato-3-phenyl propionatewith 2,3-dimethoxybenzyl isothiocyanate to give a solid product. m/z(MH⁺) 500.

EXAMPLE 124

1-[(N1-piperidinocarbothioyl-4-chlorobenzylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 124)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 4-chlorobenzylisothiocyanate to give the product as a solid. m/z (MH⁺) 527.

EXAMPLE 125

1-[(N1-piperidinocarbothioylcyclohexylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 125)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with cyclohexylisothiocyanate to give the product as a solid. m/z (MH⁺) 484

EXAMPLE 126

1-[(N1-piperidinocarbothioyltriphenylmethylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 126)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with tritylisothiocyanate to give the product as a solid. m/z (MH⁺).

EXAMPLE 127

1-(N-1-Piperidinocarbothioyl-(2-phenylbenzylamino)-4-yl)-3-(3-N-pyrrolidinopropyl)benzimidazol-2-one(Compound 127)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-phenylbenzylisothiocyanate (prepared by treating 2-phenylbenzylamine withdi(2-pyridyl)thionocarbonate following the procedure used to prepare1,1-di(p-anisyl)methyl isothiocyanate in Example 68) to give the productas a solid. m/z (MH⁺) 568

EXAMPLE 128

1-[(N1-piperidinocarbothioylpropylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 128)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with propylisothiocyanate to give the product. m/z (MH⁺) 444

EXAMPLE 129

1-[(N1-piperidinocarbothioyl-1-adamantylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 129)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 1-adamantylisothiocyanate to give the product. m/z (MH⁺) 536

EXAMPLE 130

1-[(N1-piperidinocarbothioyl-butylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 130)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with t-butylisothiocyanate to give the product. m/z (MH⁺) 444

EXAMPLE 131

1-[(N1-piperidinocarbothioylfluorenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 131)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 9-fluorenylisothiocyanate (prepared by treating 9-aminofluorene withdi(2-pyridyl)thionocarbonate following the procedure used to prepare1,1-di(p-anisyl)methyl isothiocyanate in Example 68) to give the productas a solid. m/z (MH⁺) 566

EXAMPLE 132

1-[(N1-piperidinocarbothioyl-2-isopropylphenylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 132)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with 2-isopropylphenylisothiocyanate to give the product. m/z (MH⁺) 520

EXAMPLE 133

1-[(N1-piperidinocarbothioylphenpropylamino)-4-yl]-3-(3-N-piperidinylpropyl)-1,3-dihydrobenzimidazol-2-one(Compound 133)

Compound 72, as prepared in Example 72, was treated as described inExample 81 substituting benzhydryl isothiocyanate with phenpropylisothiocyanate to give the product. m/z (MH⁺) 520

EXAMPLE 134

1-[(N1-Piperidinocarbothioyldiphenylmethylamino)-4-yl]-3-(3-cyclohexylpropyl)-1,3-dihydro-benzimidazol-2-one(Compound 134)

Compound 9, as prepared in Example 9, was treated as described inExample 10 substituting methyl iodide with cyclohexylpropylbromide togive the product. m/z (MH⁺) 567

EXAMPLE 135

1-[(N-Piperidin-1-yl)-N-(2-phenylbenzyl)guanidin-4-yl]-3-pyrrolidin-1-yl-1,3-dihydro-benzimidazol-2-one(Compound 135)

A mixture of the TFA salt of Compound 72 (0.266 g, 0.48 mM), as preparedin Example 72, 1,3-bis(tertbutoxycarbonyl)-2-methyl-2-thiopseudourea(0.138 g, 0.48 mM) and excess triethylamine (0.4 ml, 2.8 mM) was gentlyheated in a 40° C. oil bath and stirred at that temperature for threedays. The reaction mixture was cooled to room temperature, diluted withwater (40 ml) and extracted with ethyl acetate (2×50 ml). The combinedethyl acetate extracts were dried over MgSO₄, evaporated in vacuo andthe crude mixture chromatographed (EM silica gel 60, 10% MeOH in CH₂Cl₂)to give the desired guanidine intermediate (0126 g, 46%). Sodium hydride(0.007 g, 0.25 mM was them added to a cooled (0° C.) mixture of theguanidine intermediate (0.126 g, 0.22 mM) in dry DMF (5 ml). Theresulting mixture was slowly warmed up to RT, stirred at RT for 1 hourand 2-phenylbenzyl bromide was slowly added. Stirring was continued foran additional 4 hours and H₂O (40 ml) was slowly added. The aqueousmixture was extracted with ethyl acetate (2×50 ml). The combined ethylacetate extracts were dried over MgSO₄ and evaporated in vacuo. Theproduct, isolated by trituration with Et₂O, was diluted with methylenechloride (20 ml), cooled to 0° C. and TFA (2 ml) was added. The mixturewas warm up to RT then stirred at RT overnight. The mixture was dilutedwith saturated NaHCO₃ (40 ml), another (20 ml) of methylene chloride wasadded and the layers were separated. The methylene chloride layer wasagain washed with saturated NaHCO₃, dried over MgSO₄, evaporated invacuo and chromatographed (10% MeOH in CH₂Cl₂) to give the product.(MH⁺) 537.

EXAMPLE 136

V1a, V1b or V2 Binding Assay

Receptor binding studies were performed using recombinant human V1a, V1bor V2 receptors. Cellular membranes were harvested from HEK-293 cellstransfected to express either the V1a, V1b or V2 receptors. Compoundswere evaluated for their ability to displace ³H-arginine vasopressin(³H-AVP; specific activity 40-87 Ci/mmol; NEN Life Sciences, Boston,Mass.). Compounds were solubilized in dimethylsulfoxide (DMSO) anddiluted to working concentration of 10% DMSO with assay buffer (50 mMTris, 5 mM MgCl₂, 0.1% BSA, pH 7.5). Assay buffer was supplemented withseveral protease inhibitors (1 mM Pefabloc, 5 μg/mlaprotinin/leupeptin/pepstatin A, 50 μg/ml bacitracin; Sigma Chemical,St. Louis, Mo.). Non-specific binding was determined using 1.25 μMarginine vasopressin (AVP; Peninsula Labs, Belmont, Calif.). Assayreagents and test compounds were added to 96-well round bottompolypropylene plates (145 μl buffer, 5 μl compound in 10% DMSO, 25 μlbuffer containing 10,000 cpm tracer, 25 μl cell membrane). Afterincubation for 1 hour at room temperature, the well contents wereaspirated across a Unifilter GF/C plate (Packard Instrument, DownersGrove, Ill.) which had been presoaked in 0.3% polyethyleneimine toprevent peptide sticking. The wells were washed repeatedly with coldsaline containing 0.05% Tween 20. The plate was then dried and 25 μlMicroscint-20 cocktail (Packard Instruments) added to each well. Theplates were sealed and counted on a TopCount scintillation counter(Packard Instruments) using quench correction.

EXAMPLE 137

Neuropeptide Y Receptor Binding Assay

MATERIALS Cell Membranes from KAN-TS cells having NPY2 receptors¹²³I-PYY (NEN, cat. #NEX240) PYY 3-36 human, (Bachem, cat. #H-8585.0500)Buffers: Homogenization buffer: 20 mM Tris-HCl, pH 7.7 5 mM EDTA Bindingbuffer: 20 mM HEPES, pH 7.4 120 mM NaCl 0.22 mM KH₂PO₄ 1.3 mM CaCl₂ 0.8mM MgSO₄ Compound Diluent: 30% DMSO in 50 mM HEPES Wash buffer: PBS(GIBCO, cat. #14040- 133) Compounds: 400 μM in 30% DMSO/50 mM HEPES, pH7.4

Method

Load 96-well RIA racks with RIA vials (Sarstedt, cat. #73.1055)

Prepare membranes—use 2×15 cm confluent plates/96-well assay plate

Add 14 mls Homogenization buffer/cell pellet

Homogenize at high speed for 15 seconds

Transfer to 15 ml conical tube and spin 5′ at 4° C. at setting 3 inRT6000 centrifuge

Transfer supernatant to 30 ml Corex tube

Balance and spin 25′ at 15,000 rpm at 4° C.

Resuspend pellet in 10 mls Binding buffer

Homogenize at high speed for 15 sec.

Bring volume up to 50 mls in Binding buffer (25 mls/2×96-well plates)

Keep on ice until use or freeze in aliquots (2 plates/tube) in −70° C.

Prepare ¹²⁵I-PYY (for 2×96-well compound plates)

Dilute 50 uCi ¹²⁵I-PYY in 1 ml H₂O

Add 0.4 ml 10% BSA to 20 ml Binding buffer

Add 150 μl ¹²⁵I-PYY, mix well

Prepare Controls:

NSB (1 μM PYY final conc.): 40 μl PYY (100 μM stock)+60 μl 30% DMSO inHEPES=40 μM PYY—add 5 μl/well

Total Binding: Add 5 μl/well of Compound Diluent

To start reaction:

Add 5 μl compound (final conc. @10 μM)

Add 95 μl ¹²⁵I-PYY

Add 100 μl membrane

Incubate at R.T. for 1 hr.

To stop reaction:

Spin plates for 10′ at setting 9 in RT6000 centrifuge

Aspirate supernatant from tubes, add 300 μl PBS and aspirate again.

After plates are washed and aspirated, put individual tubes in 12×75 mmpolypropylene carrier tubes. Count on gamma counter.

Table I below sets forth the vasopressin receptor and neuropeptide Yreceptor binding data of some compounds of the instant invention.

TABLE I Binding IC₅₀ (μM) or % Inh @ μM No. Structure M W. NPY-2@10V1a@1.0 V1b@1.0 V2@1.0 1

442.58 52% 0.59  0%@10 38% 2

414.96 1% 21%  0%@10 7% 3

352.46 13%  0%  0%@10 7% 4

382.49 6%  0%  0%@10 0% 5

382.49 14% 38%  8%@10 34% 6

442.54 16% 20%  0%@10 9% 7

414.51 13% 9.2 11%@10 31% 8

380.47 5% 55% 13%@10 10% 10

456.61 34% 0.38 — 51% 11

366.49 26% 3.1  0%@10 3% 12

400.93 21% 2.5  0%@10 5%@10 13

456.61 22% 1.2  1%@10 4%@10 14

396.51 18%  0%  0%@10 1% 15

416.55 14% 17%  7%@10 10% 16

410.50 15% 40% 15%@10 0% 17

435.38 15% 12%  7%@10 14% 18

426.54 10% 22%  3%@10 9% 19

555.74 69% 0.27 — 42% 20

456.56 12% 25%@10  0%@10 0% 21

408.57 13% 31% — 19% 22

380.51 11% 45%  0%@10 4% 23

414.96 15% 56%  0%@10 12% 24

409.56 12% 19%  0%@10 9% 25

518.68 13%  0%  0%@10 0% 26

389.52 10% 33%  0%@10 20% 27

398.50 15% 33%  0%@10 20% 28

400.93 24% 22%  3%@10 0% 29

367.48 11% 1.9  0%@10 2% 30

428.99 23% 0.39  0%@10 9% 31

425.51 17% 19%  5%@10 15% 32

456.61 26% 42%  4%@10 9% 33

440.57 13% 33%  9%@10 0% 34

477.03 22% 42% 13%@10 21% 35

541.76 74% 0.075 47%@1 44% 36

497.68 16% 45% 20%@10 0% 37

532.71 0%  5%  8%@10 2% 38

394.54 7% 25%  0%@10 9% 39

505.08 18% 17%  7%@10 0% 40

438.55 17% 0.19 11%@10 0% 41

424.52 11%  8% — 0% 42

537.7266 10% 0.038 37%@10 0% 43

523.6997 13% 39% 16%@10 10% 44

508.6447 9% 37% 24%@10 2% 45

506.6722 15% 54% — 9% 46

566.7247 16% 8%@0.1 26%@10 0% 47

423.539 10% 45% 0%@10 14% 48

350.4204 22%  2%  3%@10 0% 49

412.4913 12% 63% 18%@10 0% 50

477.5873 16%  8% 15%@10 0% 51

438.5506 2% 25% 19%@10 1% 52

629.7803 11% 0.58 13%@10 — 54

629.7828 4% 47% 18%@10 0% 55

536.1405 82% 0.027 5.1 1.25 56

625.7486 22% 0.36 19%@10 3% 57

532.1065 20% 0.26 25%@10 0% 58

574.1469 2% 52% — — 59

541.7205 90% 0.032 62%@10 (4.1) 18% 60

542.7021 35% 49% 19%@10 0% 61

514.6484 90% 17% 22%@10 0% 62

506.04 50% 0.2 35%@10 0% 63

522.1138 94% 0.05 74%@10 (4.7) 42% 64

550.1676 93% 0.024 5.4 0.56 65

584.6124 51% 0.077 51%@10 0.5 66

502.6374 21% 15%@0.1 11%@10 0% 67

568.5696 2% 57%@0.1 45%@10 0% 68

559.73 11% 46%@0.1 66%@10 (4.6) 0% 69

513.6636 40% 22% 27%@10 0% 71

527.7339 79% 0.029 88%@10 (0.87) 0% 73

553.7718 89% 0.016 0.3 0% 74

350.4204 0%  0% 29%@10 0% 75

426.5182 12% 58% 1 0% 76

541.7174 41% 0.25 25%@10 0% 77

483.6135 10% 0.079 30%@10 0% 78

582.8133 74% 95% 41%@10 17% 79

583.8414 80% 0.016 48% 13% 80

567.7748 — 0.17 38% 11% 81

567.7986 89% 0.004 0.076 18% 82

595.8524 91% 0.006 0.14 11% 83

639.8622 79% 0.044 47% 2% 84

569.7712 73% 0.022 0.274 8% 85

555.7877 81% 0.020 0.230 8% 86

549.7375 10% 0.013 1.19 3% 87

493.6734 13% 30% 23% 3% 88

595.8524 — 0.036 1.0 3% 89

479.5979 8% 34% 10% 0 90

541.7607 13% 0.062 27% 5% 91

525.6942 56% 64% 24% 0% 92

449.5964 0%  3%  5% 3% 93

553.7718 17% 0.049 48% 0% 94

537.7051 78% 68% 33% 8% 95

553.7046 0% 0.162 23% 2% 96

537.7051 20% 0.079 43% 0% 97

551.7321 14% 0.034 35% 0% 98

595.8524 85% 0.022 0.179 0% 99

565.7589 29% 0.126 46% 16% 100

566.7467 6% 0.283 36% 24% 101

579.7858 21% 0.014 43% 0% 102

535.6893 23% 0.123 41% 6% 104

567.7986 96% 0.018 48% 14% 105

491.7009 12% 0.188 (58%) 30% 0% 106

475.6343 0% 56% 32% 2% 107

581.8255 95% 0.022 45% 12% 108

500.6648 41% 0.579 37% 16% 109

491.7009 58% 0.056 14% 0% 110

475.6343 0% 41% 19% 2% 111

521.7272 31% 0.109, 0.056 30% 0% 112

541.7607 55% 0.139 32% 0% 113

581.825 89% 0.023 (70%) 47% 7% 114

479.597 17%  1%  4% 2% 115

495.664 26% 13% 20% 11% 116

505.727 25% 85% 47% 18% 117

503.687 1% 0.331 (68%) 43% 15% 118

581.825 52% 94% 55% 21% 119

507.699 13% 0.061 (48%) 29% 19% 120

627.829 100% 20% 25% 20% 121

635.795 — 0.33 39% 3% 122

609.878 — 0.052 0.250 (70%) 0 123

537.725 — 0.43 31% 2% 124

526.145 — 0.029 44% 3% 125

483.721 — 0.39 35% 0% 126

643.8955 —  0%  0% 0% 127

567.7979 — 0.022 45% 0% 128

443.6563 — 12% 31% 0% 129

535.7965 — 0.073 53% 3% 130

457.6831 — 19% 26% 2% 131

565.7821 — 0.048 62% 0% 132

519.7539 — 66% 55% 0% 133

519.7539 — 0.069 42% 4% 134

566.8098 — 0.45 37% 0% 135

550.7468 — 24%  0% 0% 136

627.8495 — 0.079 50% 25% 137

523.7172 — 0.091 41% 0% 138

503.6869 — 58% 21% 0% 139

704.9578 —  0%  0% 0% 140

539.7443 — 59% 28% 0% 141

581.8247 — 83% 29% 0% 142

595.8515 — 0.068 56% 4% 143

565.7821 — 0.041 65% 8% 144

581.7851 — 0.395 31% 2% 145

566.8098 — 0.45 37% 0% 146

581.8247 — 85%@1 15%@0.5 33% 0% 147

565.7577 — 0.44 27% 1 148

567.7979 — 0.053 40% 1 149

551.7309 — 0.042 44% 0% 150

629.8251 — 38% 16% 0% 151

489.6601 — 62% 37% 0% 152

549.7151 — 0.23 38% 2% 153

562.7788 —  0%  0% 0% 154

478.6616 —  7%  0% 3% 155

517.7381 — 28% 10% 5% 156

521.6825 — 0.45 22% 3% 157

485.6495 —  5%  0% 6% 158

481.6615 — 55% 18% 42% 159

485.6931 —  2% 10% 0% 160

497.7285 — 0.23 27% 0% 161

553.7711 — 0.108 40% 2% 162

537.7041 — 0.117 26% 4% 163

535.7093 — 0.15 27% 0% 164

560.5905 — 0.086 35% 5% 165

534.7688 — 40% 20% 3% 166

458.628 —  5% 16% 19% 167

616.81 — 12%  1% 8% 168

492.688 — 62% 25% 2% 169

567.798 — 0.012 1.72 4% 170

650.931 — 0.080 0.68 6% 171

565.758 — 65% 33% 2% 172

581.825 — 0.072 0.70 6% 173

519.754 — 0.25 43% 0% 174

560.591 — 0.42 34% 0% 175

567.754 — 61% 23% — 176

581.781 — 59% 31% — 177

623.905 — 0.147 31% — 178

583.841 — 0.090 43% — 179

609.878 — 0.145 65% — 180

609.878 — 0.067 58% — 181

581.825 — 0.023 0.15 —

EXAMPLE 138

V1a, V1b or V2 Functional Assay

HEK-293 cells were grown in DMEM media supplemented with 10% FBS andglutamine (Gibco BRL, Grand Island, N.Y.). Once transfected the cellswere passed biweekly by trypsinization and seeded into 96 well plates at33,000 cells per well. HEK-293 were transfected with human V1a, V1b orV2 DNA using DMRIE-C reagent from Life Technologies, Inc., Grand Island,N.Y. Cells were tested for their responsiveness to vasopressin 48 hoursafter transfection. Stable lines were generated by selecting cells grownin culture media containing geneticin (500 μg/ml, Life Technologies).

The accumulation of cAMP was measured in transfected HEK-293 expressingthe human V2 receptor. The cells were cultured 4-7 days in 96-wellplates. On the day of assay, cells were washed twice in assay media(DMEM/F12 containing 0.1% BSA). The cells were treated with the testcompound for 5 minutes and then given AVP (1 nM) in assay mediacontaining 1 mM isobutylmethylxanthine. After 5 minutes, 0.5 N HCl wasadded to disrupt the cells and solubilize cAMP. The cAMP content of 20μl of the cell lysate in each well was measured using cAMP Flashplates(NEN Life Sciences). Data are expressed as pmol cAMP/well. While theassay is optimized to detect and quantitate antagonistic activity,agonistic activity would also be apparent at the higher concentrationsof test compounds.

Intracellular calcium mobilization was measured in HEK-293 cellstransfected to express either human V1a, oxytocin or V1b receptors.Cells were plated into black 96-well Packard Clear-View plates 4 to 7days prior to use. The cells were loaded with fluo-3 AM (MolecularProbes, Inc., Eugene, Oreg.) in buffer (25 mM Hepes, 125 mM NaCl, 1 gm/lglucose, 0.1% BSA, 5 mM KCl, 0.5 mM CaCl₂, 0.5 mM MgCl₂, pH 7.45)containing Pluronic (Molecular Probes) Cells were incubated with 5 μMfluo-3 AM for 1 hour shielded from light at room temperature.Intracellular fluorescence was measured using FLIPR (fluorometricimaging plate reader; Molecular Devices, Inc., Sunnyvale, Calif.). TheFLIPR protocol called for images to be collected at one second intervalswith 50 μl of the test compound added after the initial 10 images. Anadditional 70 images were then taken to detect any compound agonisticactivity. FLIPR then added 50 μl of agonist peptide and collected afinal 40 images for quantitating compound antagonistic activity. V1a-and V1b-expressing HEK cells were challenged with 1 nM and 0.5 nM AVP,respectively. Oxytocin-expressing HEK cells were challenged with 0.5 nMoxytocin (Peninsula Labs).

The data from the cAMP accumulation and the calcium mobilization assaysare expressed as IC₅₀ values as determined from dose response curves.

Table II below sets forth the vasopressin V1a, V1b receptor cell-basedfunctional activity of some compounds of the instant invention.

TABLE II Cell-Based Functional activity Compound (IC₅₀ in μM or % Inh. @μM) No. V1a V1b V2 35 0.458 9.99 0.623 42 0.81 0% @ 30 0% @ 10 55 0.1390.318 22.8 57 0.482 16.84 0% @ 30 58 1.43 0% @ 30 0% @ 30 59 0.24 6.610% @ 30 62 0.69 0 @ 30 — 63 0.31 8.06 — 64 0.14 12.1 — 65 0.46 21.0 —

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

What is claimed is:
 1. A compound of Formula (I)

wherein A is C₆₋₁₀ aryl or C₅₋₁₀ heteroaryl having 0-4 heteroatomsselected from N, O, and S; X is selected from S, O, NH, and NCN; Y is Sor O; R₁ is 1-3 groups selected from hydrogen, alkyl, substituted alkyl,halogen, nitro, methylenedioxy, nitrile, —OR^(a), —NHR^(a),—NR^(a)R^(b), —S(O)_(p)R^(a), —N(R^(a))C(O)R^(b), —C(O)OR^(a),—C(O)NR^(a)R^(b), —SO₂NR^(a)R^(b), —N(R^(a))SO₂R^(b),N(R^(a))C(O)NR^(a), and NHCOOR^(a), wherein R^(a) and R^(b) areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclyl, substitutedheterocyclyl, heteroaryl, and substituted heteroaryl; R² is selectedfrom hydrogen, alkyl, and substituted alkyl; R³ is selected fromhydrogen, alkyl, substituted alkyl, benzhydryl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, substitutedheterocyclyl, —C(O)OR^(c), and —C(O)NR^(c)R^(d), wherein R^(c) and R^(d)are independently selected from hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, and substituted heterocyclyl, or NR^(c)R^(d) may be takentogether to form a group selected from heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl; R₄ and R₅ areindependently selected from hydrogen, alkyl, alkyl substituted with arylor heteroaryl, phenyl, substituted phenyl, or R₄ and R₅ are non-existentwhen n is 0; p is from 0 to 2; n is 0 or 1; and m is 0 or 1, with theproviso that when m is 0, X is O, and R₃ is selected from heteroaryl,substituted heteroaryl, —C(O)OR^(c), and —C(O)NR^(c)R^(d) wherein R^(c)and R^(d) are independently selected from alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, and substituted heterocyclyl, or NR^(c)R^(d) may be takentogether to form a group selected from heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl, then n is 0; oran optical isomer, enantiomer, diastereomer, racemate thereof, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein X is selected from S, O, and NH.
 3. The compound of claim 1wherein A is phenyl or substituted phenyl.
 4. The compound of claim 3wherein X is S or NH.
 5. The compound of claim 1 wherein R₂ is alkylsubstituted with one or more groups selected from cycloalkyl, aryl,—NHC(NH)NR^(c)R^(d), —NR^(c)R^(d), —C(O)OR^(c), —OR^(c), —NHC(O)R^(c),and —C(O)NR^(c)R^(d), wherein R^(c) and R^(d) are independently selectedfrom hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, and substitutedheterocyclyl, or NR^(c)R^(d) may be taken together to form a groupselected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, and substituted heterocyclyl.
 6. The compoundof claim 5 wherein X is S and R₃ is aryl or substituted aryl.
 7. Thecompound of claim 1 wherein X is O and n is
 0. 8. The compound of claim1 wherein R₂ is hydrogen and X is S.
 9. The compound of claim 8 whereinR₄ and R₅ are independently phenyl or substituted phenyl.
 10. Thecompound of claim 1 which is 1-piperidinecarbothioamide,4-[3-[3-(cyclohexylmethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.11. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.12. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[2,3-dihydro-2-oxo-3-[3-(1-piperidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.13. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-[3-(dimethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.14. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[2,3-dihydro-2-oxo-3-[3-(1-pyrrolidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.15. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.16. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-[3-[(aminoiminomethyl)amino]propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.17. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.18. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-[(4-chlorophenyl)phenylmethyl]-.19. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-(3-aminopropyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.20. The compound of claim 1 which is 1-piperidinecarbothioamide,4-[3-[2-(diethylamino)ethyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-.21. The compound of claim 1 which is phenylalanine,N-[[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]carbonothioyl]-,methyl ester.
 22. The compound of claim 1 which is1-piperidinecarbothioamide,4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-(1,2-diphenylethyl)-.
 23. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.